Modulators of indoleamine 2,3-dioxygenase and methods of using the same

ABSTRACT

The present invention is directed to modulators of indoleamine 2,3-dioxygenase (IDO), as well as compositions and pharmaceutical methods thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 13/220,406 filed onAug. 29, 2011, which is a divisional of U.S. Ser. No. 11/430,441, filedMay 9, 2006, which claims the benefit of U.S. Provisional ApplicationNo. 60/679,507, filed May 10, 2005, each of which is incorporated hereinby reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to modulators of indoleamine2,3-dioxygenase (IDO), as well as compositions and pharmaceuticalmethods thereof.

BACKGROUND OF THE INVENTION

Tryptophan (Trp) is an essential amino acid required for thebiosynthesis of proteins, niacin and the neurotransmitter5-hydroxytryptamine (serotonin). The enzyme indoleamine 2,3-dioxygenase(also known as INDO or IDO) catalyzes the first and rate limiting stepin the degradation of L-tryptophan to N-formyl-kynurenine. In humancells, a depletion of Trp resulting from IDO activity is a prominentgamma interferon (IFN-γ) inducible antimicrobial effector mechanism.IFN-γ stimulation induces activation of IDO, which leads to a depletionof Trp, thereby arresting the growth of Trp-dependent intracellularpathogens such as Toxoplasma gondii and Chlamydia trachomatis. IDOactivity also has an antiproliferative effect on many tumor cells, andIDO induction has been observed in vivo during rejection of allogeneictumors, indicating a possible role for this enzyme in the tumorrejection process (Daubener, et al., 1999, Adv. Exp. Med. Biol., 467:517-24; Taylor, et al., 1991, FASEB J., 5: 2516-22).

It has been observed that HeLa cells co-cultured with peripheral bloodlymphocytes (PBLs) acquire an immuno-inhibitory phenotype throughup-regulation of IDO activity. A reduction in PBL proliferation upontreatment with interleukin-2 (IL2) was believed to result from IDOreleased by the tumor cells in response to IFNG secretion by the PBLs.This effect was reversed by treatment with 1-methyl-tryptophan (1MT), aspecific IDO inhibitor. It was proposed that IDO activity in tumor cellsmay serve to impair antitumor responses (Logan, et al., 2002,Immunology, 105: 478-87).

Recently, an immunoregulatory role of Trp depletion has received muchattention. Several lines of evidence suggest that IDO is involved ininduction of immune tolerance. Studies of mammalian pregnancy, tumorresistance, chronic infections and autoimmune diseases have shown thatcells expressing IDO can suppress T-cell responses and promotetolerance. Accelerated Trp catabolism has been observed in diseases anddisorders associated with cellular immune activation, such as infection,malignancy, autoimmune diseases and AIDS, as well as during pregnancy.For example, increased levels of IFNs and elevated levels of urinary Trpmetabolites have been observed in autoimmune diseases; it has beenpostulated that systemic or local depletion of Trp occurring inautoimmune diseases may relate to the degeneration and wasting symptomsof these diseases. In support of this hypothesis, high levels of IDOwere observed in cells isolated from the synovia of arthritic joints.IFNs are also elevated in human immunodeficiency virus (HIV) patientsand increasing IFN levels are associated with a worsening prognosis.Thus, it was proposed that IDO is induced chronically by HIV infection,and is further increased by opportunistic infections, and that thechronic loss of Trp initiates mechanisms responsible for cachexia,dementia and diarrhea and possibly immunosuppression of AIDS patients(Brown, et al., 1991, Adv. Exp. Med. Biol., 294: 425-35). To this end,it has recently been shown that IDO inhibition can enhance the levels ofvirus-specific T cells and, concomitantly, reduce the number ofvirally-infected macrophages in a mouse model of HIV (Portula et al.,2005, Blood, 106:2382-90).

IDO is believed to play a role in the immunosuppressive processes thatprevent fetal rejection in utero. More than 40 years ago, it wasobserved that, during pregnancy, the genetically disparate mammalianconceptus survives in spite of what would be predicted by tissuetransplantation immunology (Medawar, 1953, Symp. Soc. Exp. Biol. 7:320-38). Anatomic separation of mother and fetus and antigenicimmaturity of the fetus cannot fully explain fetal allograft survival.Recent attention has focused on immunologic tolerance of the mother.Because IDO is expressed by human syncytiotrophoblast cells and systemictryptophan concentration falls during normal pregnancy, it washypothesized that IDO expression at the maternal-fetal interface isnecessary to prevent immunologic rejection of the fetal allografts. Totest this hypothesis, pregnant mice (carrying syngeneic or allogeneicfetuses) were exposed to 1MT, and a rapid, T cell-induced rejection ofall allogeneic concepti was observed. Thus, by catabolizing tryptophan,the mammalian conceptus appears to suppresses T-cell activity anddefends itself against rejection, and blocking tryptophan catabolismduring murine pregnancy allows maternal T cells to provoke fetalallograft rejection (Munn, et al., 1998, Science 281: 1191-3).

Further evidence for a tumoral immune resistance mechanism based ontryptophan degradation by IDO comes from the observation that most humantumors constitutively express IDO, and that expression of IDO byimmunogenic mouse tumor cells prevents their rejection by preimmunizedmice. This effect is accompanied by a lack of accumulation of specific Tcells at the tumor site and can be partly reverted by systemic treatmentof mice with an inhibitor of IDO, in the absence of noticeable toxicity.Thus, it was suggested that the efficacy of therapeutic vaccination ofcancer patients might be improved by concomitant administration of anIDO inhibitor (Uyttenhove et al., 2003, Nature Med., 9: 1269-74). It hasalso been shown that the IDO inhibitor, 1-MT, can synergize withchemotherapeutic agents to reduce tumor growth in mice, suggesting thatIDO inhibition may also enhance the anti-tumor activity of conventionalcytotoxic therapies (Muller et al., 2005, Nature Med., 11:312-9).

One mechanism contributing to immunologic unresponsiveness toward tumorsmay be presentation of tumor antigens by tolerogenic host APCs. A subsetof human IDO-expressing antigen-presenting cells (APCs) that coexpressedCD123 (IL3RA) and CCR6 and inhibited T-cell proliferation have also beendescribed. Both mature and immature CD123-positive dendritic cellssuppressed T-cell activity, and this IDO suppressive activity wasblocked by 1MT (Munn, et al., 2002, Science 297: 1867-70). It has alsobeen demonstrated that mouse tumor-draining lymph nodes (TDLNs) containa subset of plasmacytoid dendritic cells (pDCs) that constitutivelyexpress immunosuppressive levels of IDO. Despite comprising only 0.5% oflymph node cells, in vitro, these pDCs potently suppressed T cellresponses to antigens presented by the pDCs themselves and also, in adominant fashion, suppressed T cell responses to third-party antigenspresented by nonsuppressive APCs. Within the population of pDCs, themajority of the functional IDO-mediated suppressor activity segregatedwith a novel subset of pDCs coexpressing the B-lineage marker CD19.Thus, it was hypothesized that IDO-mediated suppression by pDCs in TDLNscreates a local microenvironment that is potently suppressive of hostantitumor T cell responses (Munn, et al., 2004, J. Clin. Invest.,114(2): 280-90).

IDO degrades the indole moiety of tryptophan, serotonin and melatonin,and initiates the production of neuroactive and immunoregulatorymetabolites, collectively known as kynurenines. By locally depletingtryptophan and increasing proapoptotic kynurenines, IDO expressed bydendritic cells (DCs) can greatly affect T-cell proliferation andsurvival. IDO induction in DCs could be a common mechanism of deletionaltolerance driven by regulatory T cells. Because such tolerogenicresponses can be expected to operate in a variety of physiopathologicalconditions, tryptophan metabolism and kynurenine production mightrepresent a crucial interface between the immune and nervous systems(Grohmann, et al., 2003, Trends Immunol., 24: 242-8). In states ofpersistant immune activation, availability of free serum Trp isdiminished and, as a consequence of reduced serotonin production,serotonergic functions may also be affected (Wirleitner, et al., 2003,Curr. Med. Chem., 10: 1581-91).

Interestingly, administration of interferon-α has been observed toinduce neuropsychiatric side effects, such as depressive symptoms andchanges in cognitive function. Direct influence on serotonergicneurotransmission may contribute to these side effects. In addition,because IDO activation leads to reduced levels of tryptophan, theprecursor of serotonin (5-HT), IDO may play a role in theseneuropsychiatric side effects by reducing central 5-HT synthesis.Furthermore, kynurenine metabolites such as 3-hydroxy-kynurenine(3-OH-KYN) and quinolinic acid (QUIN) have toxic effects on brainfunction. 3-OH-KYN is able to produce oxidative stress by increasing theproduction of reactive oxygen species (ROS), and QUIN may produceoverstimulation of hippocampal N-methyl-D-aspartate (NMDA) receptors,which leads to apoptosis and hippocampal atrophy. Both ROSoverproduction and hippocampal atrophy caused by NMDA overstimulationhave been associated with depression (Wichers and Maes, 2004, J.Psychiatry Neurosci., 29: 11-17). Thus, IDO activity may play a role indepression.

Small molecule inhibitors of IDO are being developed to treat or preventIDO-related diseases such as those described above. For example, PCTPublication WO 99/29310 reports methods for altering T cell-mediatedimmunity comprising altering local extracellular concentrations oftryptophan and tryptophan metabolites, using an inhibitor of IDO such as1-methyl-DL-tryptophan, p-(3-benzofuranyl)-DL-alanine, p-[3benzo(b)thienyl]-DL-alanine, and 6-nitro-L-tryptophan) (Munn, 1999).Reported in WO 03/087347, also published as European Patent 1501918, aremethods of making antigen-presenting cells for enhancing or reducing Tcell tolerance (Munn, 2003). Compounds havingindoleamine-2,3-dioxygenase (IDO) inhibitory activity are furtherreported in WO 2004/094409; and U.S. Patent Application Publication No.2004/0234623 is directed to methods of treating a subject with a canceror an infection by the administration of an inhibitor ofindoleamine-2,3-dioxygenase in combination with other therapeuticmodalities.

In light of the experimental data indicating a role for IDO inimmunosuppression, tumor resistance and/or rejection, chronicinfections, HIV-infection, AIDS (including its manifestations such ascachexia, dementia and diarrhea), autoimmune diseases or disorders (suchas rheumatoid arthritis), and immunologic tolerance and prevention offetal rejection in utero, therapeutic agents aimed at suppression oftryptophan degradation by inhibiting IDO activity are desirable.Inhibitors of IDO can be used to activate T cells and therefore enhanceT cell activation when the T cells are suppressed by pregnancy,malignancy or a virus such as HIV. Inhibition of IDO may also be animportant treatment strategy for patients with neurological orneuropsychiatric diseases or disorders such as depression. Thecompounds, compositions and methods herein help meet the current needfor IDO modulators.

SUMMARY OF THE INVENTION

The present invention provides, inter alia, compounds of Formula I:

or pharmaceutically acceptable salt forms or prodrugs thereof.

The present invention further provides compositions comprising acompound of Formula I and a pharmaceutically acceptable carrier.

The present invention further provides methods of modulating enzymeactivity of IDO comprising contacting a compound of Formula I with theIDO.

The present invention further provides methods of treatingIDO-associated diseases, including, for example, cancer, viralinfection, depression, a neurodegenerative disorder, trauma, age-relatedcataracts, organ transplant rejection, or an autoimmune disease,comprising administering to a patient a therapeutically effective amountof a compound of Formula I.

The present invention further provides methods of altering extracellulartryptophan levels in a mammal comprising administering to the mammal aneffective amount of a compound of Formula I.

The present invention further provides methods of inhibitingimmunosuppression, such as IDO-mediated immunosuppresion, in a patientcomprising administering to the patient an effective amount of acompound of Formula I.

DETAILED DESCRIPTION

The present invention provides, inter alia, compounds of Formula I:

or pharmaceutically acceptable salt forms or prodrugs thereof, wherein:

Ring A is carbocyclyl or heterocyclyl optionally substituted by 1, 2, 3,4 or 5 R⁶;

W, X¹, X², Y¹, and Y² are independently selected from (CR^(a)R^(b))_(t),(CR^(a)R^(b))_(u)O(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)O(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(S)(CR^(a)R^(b))_(u),(CR^(a)R^(b))_(u)C(S)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)₂(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)₂NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)NR^(c)(CR^(a)R^(b))_(v), and(CR^(a)R^(b))_(u)C(═NR^(d))NR^(c)(CR^(a)R^(b))_(v);

R¹ is H, C(O)R⁷, C(O)NR^(8a)R^(8b), C(O)OR⁸, C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, or heterocycloalkylalkyl;

R² is H, C₁₋₆ alkyl, or C₃₋₇ cycloalkyl;

R^(3a), R^(4a), and R^(5a) are independently selected from C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, cycloalkyl, heteroaryl, andheterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy¹, CN, NO₂, OR^(e1), SR^(e1),C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1);

R^(3b), R^(4b), and R^(5b) are independently selected from H, C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, cycloalkyl, heteroaryl, andheterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂, OR^(e1),SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)R^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1);

or R² and —(R^(3a))_(a)—(W)_(b)—R^(3b) together with the N atom to whichthey are attached form a 4- to 20-membered heterocycloalkyl groupoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄haloalkyl, Cy³, CN, NO₂, OR^(e1), SR^(e1), C(O)R^(f1),C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1), OC(O)NR^(g1)R^(h1),NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1), NR^(g1)C(O)R^(f1),NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), or S(O)₂NR^(g1)R^(h1);

or —(Y¹)_(q)—(R^(4a))_(r)—(Y²)_(s)—R^(4b) and—(X¹)_(m)—(R^(5a))_(n)—(X²)_(p)—R^(5b) together with the N atom to whichthey are attached form a 4- to 20-membered heterocycloalkyl groupoptionally substituted by 1, 2, 3, 4 or 5 substituents selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy⁴, CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(NR^(i))NR^(g1)R^(h1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1);

R⁶ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂,OR^(e2), SR^(e2), C(O)R^(f2), C(O)NR^(g2)R^(h2), C(O)OR^(e2),OC(O)R^(f2), OC(O)NR^(g2)R^(h2), NR^(g2)R^(h2), NR^(g2)C(O)R^(f2),NR^(g2)C(O)OR^(e2), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f2))₂, P(OR^(e2))₂,P(O)R^(e2)R^(f2), P(O)OR^(e2)OR^(f2), S(O)R^(f2), S(O)NR^(g2)R^(h2),S(O)₂R^(f2), or S(O)₂NR^(g2)R^(h2);

R⁷ and R⁸ are independently selected from H, C₁₋₈ alkyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, each optionally substitutedby one or more substitutents independently selected from halo, CN, NO₂,OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino, C₂₋₈dialkylamino, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R^(8a) and R^(8b) are independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, andcycloalkylalkyl;

Cy¹, Cy², Cy³, and Cy⁴ are independently selected from aryl, heteroaryl,cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2,3, 4 or 5 substituents independently selected from halo, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(e3), SR^(e3),C(O)R^(f3), C(O)NR^(g3)R^(h3), C(O)OR^(e3), OC(O)R^(f3),OC(O)NR^(g3)R^(h3), NR^(g3)R^(h3), NR^(g3)C(O)R^(h3),NR^(g3)C(O)OR^(e3), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f3))₂, P(OR^(e3))₂,P(O)R^(e3)R^(f3), P(O)OR^(e3)OR^(f3), S(O)R^(f3), S(O)NR^(g3)R^(h3),S(O)₂R^(f3), and S(O)₂NR^(g3)R^(h3);

R^(a) and R^(b) are independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂, OR^(e4), SR^(e4),C(O)R^(f4), C(O)NR^(g4)R^(h4), C(O)OR^(e4), OC(O)R^(f4),OC(O)NR^(g4)R^(h4), NR^(g4)R^(h4), NR^(g4)C(O)R^(h4),NR^(g4)C(O)OR^(e4), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f4))₂, P(OR^(e4))₂,P(O)R^(e4)R^(f4), P(O)OR^(e4)OR^(f4), S(O)R^(f4), S(O)NR^(g4)R^(h4),S(O)₂R^(f4), and S(O)₂NR^(g4)R^(h4);

R^(c) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;

R^(d) is H, OR^(d1), CN or NO₂;

R^(d1) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;

R^(e1), R^(e2), R^(e3), and R^(e4) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, (C₁₋₆ alkoxy)-C₁₋₆ alkyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl;

R^(f1), R^(f2), R^(f3), and R^(f4) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl and heterocycloalkyl;

R^(g1), R^(g2), R^(g3), and R^(g4) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, arylalkyl, and cycloalkylalkyl;

R^(h1), R^(h2), R^(h3), and R^(h4) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, arylalkyl, and cycloalkylalkyl;

or R^(g1) and R^(h1) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

or R^(g2) and R^(h3) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

or R^(g3) and R^(h3) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

or R^(g4) and R^(h4) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

R^(i) is H, CN, or NO₂;

a is 0 or 1;

b is 0 or 1;

m is 0 or 1;

n is 0 or 1;

p is 0 or 1;

q is 0 or 1;

r is 0 or 1;

s is 0 or 1;

t is 1, 2, 3, 4, 5 or 6;

u is 0, 1, 2, 3, 4, 5 or 6; and

v is 0, 1, 2, 3, 4, 5 or 6.

In some embodiments, when Ring A is

R² is H;

—(Y¹)_(q)—(R^(4a))_(r)—(Y²)_(s)—R^(4b) is H; and

—(X¹)_(m)—(R^(5a))_(n)—(X²)_(p)—R^(5b) is H;

then —(R^(3a))_(a)—(W)—R^(3b) is other than:

-   -   i) phenyl, 4-iodophenyl, 4-chlorophenyl, 4-bromophenyl,        4-methylphenyl, 3-methylphenyl, 2-methylphenyl,        2,4-dimethylphenyl, 2,6-dimethylphenyl, 2,5-dimethylphenyl,        3,4-dimethylphenyl, 2-methoxyphenyl, or        2-dimethylamino-5-nitrophenyl;    -   ii) —CH₂CH₂NR^(x)R^(y), wherein each R^(x) and R^(y) is,        independently, H, ethyl, —C(O)-oxadiazole optionally substituted        with amino, or phenyl optionally having at least one substituent        which is nitro; or    -   iii) C₁₋₃ alkyl, —C(O)—(C₁₋₄ haloalkyl), naphthyl, or benzyl.

In some embodiments, when Ring A is phenyl having at least twosubstituents which are methyl;

-   -   —(Y¹)_(q)—(R^(4a))_(r)—(Y²)_(s)—R^(4b) is H; and    -   —(X¹)_(m)—(R^(5a))_(n)—(X²)_(p)—R^(5b) is H;

then —(R^(3a))_(a)—(W)—R^(3b) is other than unsubstituted phenyl.

In some embodiments, when Ring A is phenyl having at least onesubstitutent which is nitro;

-   -   —(Y¹)_(q)—(R^(4a))_(r)—(Y²)_(s)—R^(4b) is H; and    -   —(X¹)_(m)—(R^(5a))_(n)—(X²)_(p)—R^(5b) is H;

then —(R^(3a))_(a)—(W)—R^(3b) is other than pyrazolyl substituted byC₁₋₄ alkyl.

In some embodiments, when Ring A is

R² is H;

—(Y¹)_(q)—(R^(4a))_(r)—(Y²)_(s)—R^(4b) is H; and

—(X¹)_(m)—(R^(5a))_(n)—(X²)_(p)—R^(5b) is H;

then —(R^(3a))_(a)—(W)—R^(3b) is other than:

-   -   i) phenyl optionally substituted by 1 or 2 substituents selected        from halo, C₁₋₄ alkyl, and C₁₋₄ alkoxy;    -   ii) CH₂CH₂NR^(x)R^(y), wherein each R^(x) and R^(y) is,        independently, H, C₁₋₄ alkyl, —C(O)— heteroaryl optionally        substituted with amino, or phenyl optionally substituted with 1        or 2 nitro or 1 or 2 halo; or    -   iii) C₁₋₄ alkyl, —C(O)—(C₁₋₄ haloalkyl), naphthyl, or benzyl.

In some embodiments, when r is 0, then the sum of q and s is 0 or 1.

In some embodiments, when n is 0, then the sum of m and p is 0 or 1.

In some embodiments, Ring A is heterocyclyl optionally substituted by 1,2, 3, 4 or 5 R⁶.

In some embodiments, Ring A is 5- or 6-membered heterocyclyl optionallysubstituted by 1, 2, 3, 4 or 5 R⁶.

In some embodiments, Ring A is 5-membered heterocyclyl optionallysubstituted by 1, 2, 3, 4 or 5 R⁶.

In some embodiments, Ring A is 5-membered heterocyclyl containing atleast one ring-forming N atom and Ring A is optionally substituted by 1,2, 3, 4 or 5 R⁶.

In some embodiments, Ring A is 5-membered heterocyclyl containing atleast one ring-forming O atom and Ring A is optionally substituted by 1,2, 3, 4 or 5 R⁶.

In some embodiments, Ring A is 5-membered heterocyclyl containing atleast one ring-forming O atom and containing at least one ring-forming Natom, and Ring A is optionally substituted by 1, 2, 3, 4 or 5 R⁶.

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, R¹ is H, C(O)R⁷, C(O)OR⁸, C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, or heterocycloalkylalkyl.

In some embodiments, R¹ is H, C(O)R⁷, C(O)NR^(8a)R^(8b), or C(O)OR⁸.

In some embodiments, R¹ is H, C(O)R⁷, or C(O)OR⁸.

In some embodiments, R¹ is H.

In some embodiments, R² is H.

In some embodiments, R^(3a) is aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂, OR^(e1),SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(e1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, R^(3a) is aryl or heteroaryl each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, Cy², CN, NO₂, OR^(e1), SR^(e1), C(O)R^(f1),C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1), OC(O)NR^(g1)R^(h1),NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1), NR^(g1)C(O)R^(f1),NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, R^(3a) is phenyl optionally substituted by 1, 2, 3,4 or 5 substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂,OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, R^(3b) is aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂, OR^(e1),SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, R^(3b) is aryl or heteroaryl each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, Cy², CN, NO₂, OR^(e1), SR^(e1), C(O)R^(f1),C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1), OC(O)NR^(g1)R^(h1),NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1), NR^(g1)C(O)R^(f1),NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, R^(3b) is phenyl optionally substituted by 1, 2, 3,4 or 5 substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂,OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, R^(3b) is aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy², CN, NO₂, OR^(e1), SR^(e1),C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, R^(3b) is aryl or heteroaryl each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy², CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)R^(f1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, R^(3b) is phenyl optionally substituted by 1, 2, 3,4 or 5 substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy², CN, NO₂, OR^(e1), SR^(e1),C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, W is (CR^(a)R^(b))_(t),(CR^(a)R^(b))_(u)O(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)NR^(c)(CR^(a)R^(b))_(v), or(CR^(a)R^(b))_(u)C(O)O(CR^(a)R^(b))_(v).

In some embodiments, W is (CR^(a)R^(b))_(t) or(CR^(a)R^(b))_(u)O(CR^(a)R^(b))_(v).

In some embodiments, Y¹ is (CR^(a)R^(b))_(t),(CR^(a)R^(b))_(u)C(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)NR^(c)(CR^(a)R^(b))_(v), or(CR^(a)R^(b))_(u)C(O)O(CR^(a)R^(b))_(v).

In some embodiments, Y¹ is (CR^(a)R^(b))_(t) or(CR^(a)R^(b))_(u)C(O)(CR^(a)R^(b))_(v).

In some embodiments, X¹ is (CR^(a)R^(b))_(t),(CR^(a)R^(b))_(u)C(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)NR^(c)(CR^(a)R^(b))_(v), or(CR^(a)R^(b))_(u)C(O)O(CR^(a)R^(b))_(v).

In some embodiments, X¹ is (CR^(a)R^(b))_(t) or(CR^(a)R^(b))_(u)C(O)(CR^(a)R^(b))_(v).

In some embodiments, R^(4a) is C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈alkynyl, each optionally substituted by 1, 2, 3, 4 or 5 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, Cy¹, CN, NO₂, OR^(e1), SR^(e1), C(O)R^(f1),C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1), OC(O)NR^(g1)R^(h1),NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1), NR^(g1)C(O)R^(f1),NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)R^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, R^(4a) is aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy¹, CN, NO₂, OR^(e1), SR^(e1),C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, R^(5a) is C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈alkynyl, each optionally substituted by 1, 2, 3, 4 or 5 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, Cy¹, CN, NO₂, OR^(e1), SR^(e1), C(O)R^(f1),C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1), OC(O)NR^(g1)R^(h1),NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1), NR^(g1)C(O)R^(f1),NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, R^(5a) is aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy¹, CN, NO₂, OR^(e1), SR^(e1),C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)_(2R) ^(f1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, R^(4b) is H, C₁₋₈ alkyl, C₂₋₈ alkenyl, or C₂₋₈alkynyl, each optionally substituted by 1, 2, 3, 4 or 5 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, Cy^(t), CN, NO₂, OR^(e1),SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)NR^(g1)R^(h1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, R^(4b) is aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂, OR^(e1),SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, R^(4b) is H.

In some embodiments, R^(5b) is H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, eachoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂, OR^(e1), SR^(e1),C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, R^(5b) is H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, eachoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄haloalkyl, Cy², CN, NO₂, OR^(e1), SR^(e1), C(O)R^(f1),C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1), OC(O)NR^(g1)R^(h1),NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1), NR^(g1)C(O)R^(f1),NR^(g1)C(O)OR^(e1), P(R^(f1))₂, P(OR^(e1))₂, P(O)R^(e1)R^(f1),P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1), S(O)₂R^(f1), andS(O)₂NR^(g1)R^(h1).

In some embodiments, R^(5b) is H.

In some embodiments, R^(4b) is H and R^(5b) is H, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂, OR^(e1),SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)NR^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, R^(4b) is H and R^(5b) is H, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy², CN, NO₂, OR^(e1), SR^(e1),C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(hi), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, —(Y¹)_(q)—(R^(4a))_(r)—(Y²)_(s)—R^(4b) is H and—(X¹)_(m)—(R^(5a))_(n)—(X²)_(p)—R^(5b) is H.

In some embodiments, a and b are both 0.

In some embodiments, r and s are both 0.

In some embodiments, q, r, and s are all 0.

In some embodiments, n and p are both 0.

In some embodiments, a is 0.

In some embodiments, a is 1.

In some embodiments, b is 0.

In some embodiments, b is 1.

In some embodiments, q is 0.

In some embodiments, q is 1.

In some embodiments, r is 0.

In some embodiments, r is 1.

In some embodiments, s is 0.

In some embodiments, s is 1.

In some embodiments, m is 0.

In some embodiments, m is 1.

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, p is 0.

In some embodiments, p is 1.

In some embodiments, t is 1.

In some embodiments, t is 2.

In some embodiments, t is 3.

In some embodiments, t is 4.

In some embodiments, u is 0.

In some embodiments, u is 1.

In some embodiments, u is 2.

In some embodiments, u is 3.

In some embodiments, v is 0.

In some embodiments, v is 1.

In some embodiments, v is 2.

In some embodiments, v is 3.

In some embodiments, the compounds of the invention have Formula II:

wherein:

X¹ is (CR^(a)R^(b))_(t) or (CR^(a)R^(b))_(u)C(O)(CR^(a)R^(b))_(v);

R^(3a) is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, cycloalkyl,heteroaryl, or heterocycloalkyl, each optionally substituted by 1, 2, 3,4 or 5 substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy¹, CN, NO₂, OR^(e1), SR^(e1),C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)_(2R) ^(f1), and S(O)₂NR^(g1)R^(h1);

R^(3b) is H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, cycloalkyl,heteroaryl, or heterocycloalkyl, each optionally substituted by 1, 2, 3,4 or 5 substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy², CN, NO₂, OR^(e1), SR^(e1),C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1);

R^(5b) is H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, cycloalkyl,heteroaryl, or heterocycloalkyl, each optionally substituted by 1, 2, 3,4 or 5 substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy², CN, NO₂, OR^(e1), SR^(e1),C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1);

Cy¹ and Cy² are independently selected from aryl, heteroaryl,cycloalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3,4 or 5 substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(e3), SR^(e3),C(O)R^(e3), C(O)NR^(g3)R^(h3), C(O)OR^(e3), OC(O)R^(e3),OC(O)NR^(g3)R^(h3), NR^(g3)R^(h3), NR^(g3)C(O)R^(h3),NR^(g3)C(O)OR^(e3), P(R^(f3))₂, P(OR^(e3))₂, P(O)R^(e3)R^(f3),P(O)OR^(e3)OR^(f3), S(O)R^(f3), S(O)NR^(g3)R^(h3), S(O)_(2R) ^(f3), andS(O)₂NR^(g3)R^(h3);

R^(a) and R^(b) are independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂, OR^(e4), SR^(e4),C(O)R^(e4), C(O)NR^(g4)R^(h4), C(O)OR^(e4), OC(O)R^(f4),OC(O)NR^(g4)R^(h4), NR^(g4)R^(h4), NR^(g4)C(O)R^(h4),NR^(g4)C(O)OR^(e4), P(R^(e4))₂, P(OR^(e4))₂, P(O)R^(e4)R^(e4),P(O)OR^(e4)OR^(e4), S(O)R^(e4), S(O)NR^(g4)R^(h4), S(O)_(2R) ^(f4), andS(O)₂NR^(g4)R^(h4);

R^(e1), R^(e3), and R^(e4) are independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, (C₁₋₆ alkoxy)-C₁₋₆ alkyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl;

R^(f1), R^(f3), and R^(f4) are independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl and heterocycloalkyl;

R^(g1), R^(g3), and R^(g4) are independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,arylalkyl, and cycloalkylalkyl;

R^(h1), R^(h3), and R^(h4) are independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,arylalkyl, and cycloalkylalkyl;

or R^(g1) and R^(h1) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

or R^(g3) and R^(h3) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

or R^(g4) and R^(h4) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

a is 0 or 1;

m is 0 or 1;

t is 1, 2, 3, 4, 5 or 6;

u is 0, 1, 2, 3, 4, 5 or 6; and

v is 0, 1, 2, 3, 4, 5 or 6.

In some embodiments of Formula II, when —(X¹)_(m)—R^(5h) is H; then—(R^(3a))_(a)—R^(3b) is other than:

-   -   i) phenyl, 4-iodophenyl, 4-chlorophenyl, 4-bromophenyl,        4-methylphenyl, 3-methylphenyl, 2-methylphenyl,        2,4-dimethylphenyl, 2,6-dimethylphenyl, 2,5-dimethylphenyl,        3,4-dimethylphenyl, 2-methoxyphenyl, or        2-dimethylamino-5-nitrophenyl;    -   ii) —CH₂CH₂NR^(x)R^(y), wherein each R^(x) and R^(y) is,        independently, H, ethyl, —C(O)— oxadiazole optionally        substituted with amino, or phenyl optionally having at least one        substituent which is nitro; or    -   iii) C₁₋₃ alkyl, —C(O)—(C₁₋₄ haloalkyl), naphthyl, or benzyl.

In some embodiments, R^(3a) is C₁₋₈ alkyl.

In some embodiments, R^(3b) is aryl or heteroaryl, each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy², CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, R^(5b) is H, aryl, or heteroaryl, each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy², CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)NR^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(h1), and S(O)₂NR^(g1)R^(h1).

In some embodiments, the compounds of the invention have Formula I:

wherein:

Ring A is a 5-membered carbocyclyl or heterocyclyl ring optionallysubstituted by 1, 2, 3, 4 or 5 R⁶;

W, X¹, X², Y¹, and Y² are independently selected from (CR^(a)R^(b))_(t),(CR^(a)R^(b))_(u)O(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)O(CR^(a)R^(b))_(v),(CR^(a)R^(i))_(u)C(S)(CR^(a)R^(b))_(u),(CR^(a)R^(b))_(u)C(S)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)₂(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)₂NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)NR^(c)(CR^(a)R^(b))_(v), and(CR^(a)R^(b))_(u)C(═NR^(d))NR^(c)(CR^(a)R^(b))_(v);

R¹ is H, C(O)R⁷, C(O)NR^(8a)R^(8b), C(O)OR⁸, C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, or heterocycloalkylalkyl;

R² is H, C₁₋₆ alkyl, or C₃₋₇ cycloalkyl;

R^(3a), R^(4a), and R^(5a) are independently selected from C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy¹, CN, NO₂, OR^(e1), SR^(e1),C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1);

R^(3b) is H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, cycloalkyl,heteroaryl, or heterocycloalkyl, each optionally substituted by 1, 2, 3,4 or 5 substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂,OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1);

R^(4b) is H;

R^(5b) is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, cycloalkyl,heteroaryl, or heterocycloalkyl, each optionally substituted by 1, 2, 3,4 or 5 substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂,OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1);

or R² and —(R^(3a))_(a)—(W)_(b)—R^(3b) together with the N atom to whichthey are attached form a 4- to 20-membered heterocycloalkyl groupoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄haloalkyl, Cy³, CN, NO₂, OR^(e1), SR^(e1), C(O)R^(f1),C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1), OC(O)NR^(g1)R^(h1),NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1), NR^(g1)C(O)R^(f1),NR^(g1)C(O)OR^(e1), S(O)R^(f1), S(O)NR^(g1)R^(h1), S(O)₂R^(f1), andS(O)₂NR^(g1)R^(h1);

or —(Y¹)_(q)—(R^(4a))_(r)—(Y²)_(s)—R^(4b) and—(X¹)_(m)—(R^(5a))_(n)—(X²)_(p)—R^(5b) together with the N atom to whichthey are attached form a 4- to 20-membered heterocycloalkyl groupoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄haloalkyl, Cy⁴, CN, NO₂, OR^(e1), SR^(e1), C(O)R^(f1),C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1), OC(O)NR^(g1)R^(h1),NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1), NR^(g1)C(O)R^(f1),NR^(g1)C(O)OR^(e1), S(O)R^(f1), S(O)NR^(g1)R^(h1), S(O)₂R^(f1), andS(O)₂NR^(g1)R^(h1);

R⁶ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂,OR^(e2), SR^(e2), C(O)R^(f2), C(O)NR^(g2)R^(h2), C(O)OR^(e2),OC(O)R^(f2), OC(O)NR^(g2)R^(h2), NR^(g2)R^(h2), NR^(g2)C(O)R^(f2),NR^(g2)C(O)OR^(e2), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f2))₂, P(OR^(e2))₂,P(O)R^(e2)R^(f2), P(O)OR^(e2)OR^(f2), S(O)R^(f2), S(O)NR^(g2)R^(h2),S(O)₂R^(f2), or S(O)₂NR^(g2)R^(h2);

R⁷ and R⁸ are independently selected from H, C₁₋₈ alkyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, each optionally substitutedby one or more substituents independently selected from halo, CN, NO₂,OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino, C₂₋₈dialkylamino, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R^(8a) and R^(8b) are independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, andcycloalkylalkyl;

Cy¹, Cy², Cy¹, and Cy⁴ are independently selected from aryl, heteroaryl,cycloalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3,4, or 5 substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(e3), SR^(e3),C(O)R^(f3), C(O)NR^(g3)R^(h3), C(O)OR^(e3), OC(O)R^(f3),OC(O)NR^(g3)R^(h3), NR^(g3)R^(h3), NR^(g3)C(O)R^(h3),NR^(g3)C(O)OR^(e3), S(O)R^(f3), S(O)NR^(g3)R^(h3), S(O)₂R^(f3), andS(O)₂NR^(g3)R^(h3);

R^(a) and R^(b) are independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂, OR^(e4), SR^(e4),C(O)R^(f4), C(O)NR^(g4)R^(h4), C(O)OR^(e4), OC(O)R^(f4),OC(O)NR^(g4)R^(h4), NR^(g4)R^(h4), NR^(g4)C(O)R^(h4),NR^(g4)C(O)OR^(e4), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f4))₂, P(OR^(e4))₂,P(O)R^(e4)R^(f4), P(O)OR^(e4)OR^(f4), S(O)R^(f4), S(O)NR^(g4)R^(h4),S(O)₂R^(f4), and S(O)₂NR^(g4)R^(h4);

R^(c) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;

R^(d) is H, OR^(d1), CN or NO₂;

R^(d1) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;

R^(e1), R^(e2), R^(e3), and R^(e4) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, (C₁₋₆ alkoxy)-C₁₋₆ alkyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl;

R^(f1), R^(f2), R^(f3), and R^(f4) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl or heterocycloalkyl;

R^(g1), R^(g2), R^(g3), and R^(g4) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, arylalkyl, or cycloalkylalkyl;

R^(h1), R^(h2), R^(h3), and R^(h4) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, arylalkyl, or cycloalkylalkyl;

or R^(g1) and R^(h1) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

or R^(g2) and R^(h2) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

or R^(g3) and R^(h3) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

or R^(g4) and R^(h4) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

R^(i) is H, CN, or NO₂;

a is 0 or 1;

b is 0 or 1;

m is 0 or 1;

n is 0 or 1;

p is 0 or 1;

q is 0;

r is 0;

s is 0;

t is 1, 2, 3, 4, 5 or 6;

u is 0, 1, 2, 3, 4, 5 or 6; and

v is 0, 1, 2, 3, 4, 5 or 6.

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

It is further intended that the compounds of the invention are stable.As used herein “stable” refers to a compound that is sufficiently robustto survive isolation to a useful degree of purity from a reactionmixture, and preferably capable of formulation into an efficacioustherapeutic agent.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

As used herein, the term “alkyl” is meant to refer to a saturatedhydrocarbon group which is straight-chained or branched. Example alkylgroups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like. An alkyl group cancontain from 1 to about 20, from 2 to about 20, from 1 to about 10, from1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3carbon atoms.

As used herein, “alkenyl” refers to an alkyl group having one or moredouble carbon-carbon bonds. Example alkenyl groups include ethenyl,propenyl, and the like.

As used herein, “alkynyl” refers to an alkyl group having one or moretriple carbon-carbon bonds. Example alkynyl groups include ethynyl,propynyl, and the like.

As used herein, “haloalkyl” refers to an alkyl group having one or morehalogen substituents. Example haloalkyl groups include CF₃, C₂F₅, CHF₂,CCl₃, CHCl₂, C₂Cl₅, and the like.

As used herein, “carbocyclyl” groups are saturated (i.e., containing nodouble or triple bonds) or unsaturated (i.e., containing one or moredouble or triple bonds) cyclic hydrocarbon moieties. Carbocyclyl groupscan be mono- or polycyclic (e.g., having 2, 3 or 4 fused rings orspirocycles). Example carbocyclyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl,1,3-cyclopentadienyl, cyclohexenyl, norbornyl, norpinyl, norcarnyl,adamantyl, phenyl, and the like. Carbocyclyl groups can be aromatic(e.g., “aryl”) or non-aromatic (e.g., “cycloalkyl”). In someembodiments, carbocyclyl groups can have from about 3 to about 30 carbonatoms, about 3 to about 20, about 3 to about 10, or about 3 to about 7carbon atoms.

As used herein, “aryl” refers to monocyclic or polycyclic (e.g., having2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example,phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and thelike. In some embodiments, aryl groups have from 6 to about 20 carbonatoms.

As used herein, “cycloalkyl” refers to non-aromatic carbocyclesincluding cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groupscan include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings)ring systems, including spirocycles. In some embodiments, cycloalkylgroups can have from 3 to about 20 carbon atoms, 3 to about 14 carbonatoms, 3 to about 10 carbon atoms, or 3 to 7 carbon atoms. Cycloalkylgroups can further have 0, 1, 2, or 3 double bonds and/or 0, 1, or 2triple bonds. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, for example, benzo derivatives ofpentane, pentene, hexane, and the like. One or more ring-forming carbonatoms of a cycloalkyl group can be oxidized, for example, having an oxoor sulfide substituent. Example cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl,cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl,norcarnyl, adamantyl, and the like.

As used herein, “heterocyclyl” or “heterocycle” refers to a saturated orunsaturated cyclic group wherein one or more of the ring-forming atomsis a heteroatom such as O, S, or N. Heterocyclyl groups include mono- orpolycyclic ring systems. Heterocyclyl groups can be aromatic (e.g.,“heteroaryl”) or non-aromatic (e.g., “heterocycloalkyl”). Heterocyclylgroups can be characterized as having 3-14, 3-12, 3-10, 3-7, or 3-6ring-forming atoms. In some embodiments, heterocyclyl groups cancontain, in addition to at least one heteroatom, from about 1 to about13, about 2 to about 10, or about 2 to about 7 carbon atoms and can beattached/linked through either a carbon atom or a heteroatom. In furtherembodiments, the heteroatom can be oxidized (e.g., have an oxo orsulfido substituent) or a nitrogen atom can be quaternized. Examples ofheterocyclyl groups include morpholino, thiomorpholino, piperazinyl,tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl,1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl,isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl,thiazolidinyl, imidazolidinyl, and the like, as well as any of thegroups listed below for “heteroaryl” and “heterocycloalkyl.” Furtherexample heterocycles include pyrimidinyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,3,6-dihydropyridyl, 1,2,3,6-tetrahydropyridyl,1,2,5,6-tetrahydropyridyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thia-diazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,xanthenyl, octahydro-isoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzo-thiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolinyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, deca-hydroquinolinyl, 2H,6H-1,5,2dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl and isoxazolyl. Further examples of heterocycles includeazetidin-1-yl, 2,5-dihydro-1H-pyrrol-1-yl, piperindin-1yl,piperazin-1-yl, pyrrolidin-1-yl, isoquinol-2-yl, pyridin-1-yl,3,6-dihydropyridin-1-yl, 2,3-dihydroindol-1-yl,1,3,4,9-tetrahydrocarbolin-2-yl, thieno[2,3-c]pyridin-6-yl,3,4,10,10a-tetrahydro-1H-pyrazino indol-2-yl,1,2,4,4a,5,6-hexahydro-pyrazino[1,2-a]quinolin-3-yl,pyrazino[1,2-a]quinolin-3-yl, diazepan-1-yl,1,4,5,6-tetrahydro-2H-benzo[f]isoquinolin-3-yl,1,4,4a,5,6,10b-hexahydro-2H-benzo[f]isoquinolin-3-yl,3,3a,8,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-2-yl, and2,3,4,7-tetrahydro-1H-azepin-1-yl, azepan-1-yl.

As used herein, a “heteroaryl” group refers to an aromatic heterocyclehaving at least one heteroatom ring member such as sulfur, oxygen, ornitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g.,having 2, 3 or 4 fused rings) systems. Any ring-forming N atom in aheteroaryl group can also be oxidized to form an N-oxo moiety. Examplesof heteroaryl groups include without limitation, pyridyl, N-oxopyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl,isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl,benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl,triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl,benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and thelike. In some embodiments, the heteroaryl group has from 1 to about 20carbon atoms, and in further embodiments from about 3 to about 20 carbonatoms. In some embodiments, the heteroaryl group contains 3 to about 14,3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, theheteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

As used herein, “heterocycloalkyl” refers to a non-aromatic heterocyclewhere one or more of the ring-forming atoms is a heteroatom such as anO, N, or S atom. Heterocycloalkyl groups can include mono- or polycyclic(e.g., having 2, 3 or 4 fused rings) ring systems as well asspirocycles. Example “heterocycloalkyl” groups include morpholino,thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl,2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Ring-formingcarbon atoms and heteroatoms of a heterocycloalkyl group can beoptionally substituted by oxo or sulfido. Also included in thedefinition of heterocycloalkyl are moieties that have one or morearomatic rings fused (i.e., having a bond in common with) to thenonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl,and benzo derivatives of heterocycles such as indolene and isoindolenegroups. In some embodiments, the heterocycloalkyl group has from 1 toabout 20 carbon atoms, and in further embodiments from about 3 to about20 carbon atoms. In some embodiments, the heterocycloalkyl groupcontains 3 to about 20, 3 to about 14, 3 to about 7, or 5 to 6ring-forming atoms. In some embodiments, the heterocycloalkyl group has1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments,the heterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, andiodo.

As used herein, “haloalkyl” refers to an alkyl group substituted by atleast one halogen atom. Example haloalkyl groups include fluoromethyl,difluoromethyl, trifluoromethyl, and the like.

As used herein, “alkoxy” refers to an —O-alkyl group. Example alkoxygroups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like.

As used herein, “alkoxyalkyl” refers to an alky group substituted by analkoxy group.

As used here, “haloalkoxy” refers to an O-haloalkyl group. An examplehaloalkoxy group is OCF₃.

As used herein, “arylalkyl” refers to alkyl substituted by aryl and“cycloalkylalkyl” refers to alkyl substituted by cycloalkyl. An examplearylalkyl group is benzyl.

As used herein, “heteroarylalkyl” refers to alkyl substituted byheteroaryl and “heterocycloalkylalkyl” refers to alkyl substituted byheterocycloalkyl.

As used herein, “amino” refers to NH₂.

As used herein, “alkylamino” refers to an amino group substituted by analkyl group.

As used herein, “dialkylamino” refers to an amino group substituted bytwo alkyl groups.

It is understood that when a substituent is depicted structurally as alinking moiety, it is necessarily minimally divalent. For example, whenthe variable R^(3a) of the structure depicted in Formula I is alkyl, thealkyl moiety is understood to be an alkyl linking moiety such as —CH₂—,—CH₂CH₂—, CH₃CH<, etc.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. Cis and trans geometric isomers of the compounds of thepresent invention are described and may be isolated as a mixture ofisomers or as separated isomeric forms.

Compounds of the invention also include tautomeric forms, such asketo-enol tautomers.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17^(th) ed., Mack Publishing Company, Easton,Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977),each of which is incorporated herein by reference in its entirety.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes prodrugs of the compounds describedherein. As used herein, “prodrugs” refer to any covalently bondedcarriers which release the active parent drug when administered to amammalian subject. Prodrugs can be prepared by modifying functionalgroups present in the compounds in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompounds. Prodrugs include compounds wherein hydroxyl, amino,sulfhydryl, or carboxyl groups are bonded to any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl,amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compounds ofthe invention. Preparation and use of prodrugs is discussed in T.Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 ofthe A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are hereby incorporated by referencein their entirety.

Synthesis

The compounds of the present invention can be prepared in a variety ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods ashereinafter described below, together with synthetic methods known inthe art of synthetic organic chemistry or variations thereon asappreciated by those skilled in the art.

The compounds of this invention can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given; other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C) infrared spectroscopy, spectrophotometry(e.g., UV-visible), or mass spectrometry, or by chromatography such ashigh performance liquid chromatograpy (HPLC) or thin layerchromatography.

Preparation of compounds can involve the protection and deprotection ofvarious chemical groups. The need for protection and deprotection, andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Greene, et al., Protective Groups in OrganicSynthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated herein byreference in its entirety.

The reactions of the processes described herein can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,i.e., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a “chiral resolving acid” which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids. Resolution ofracemic mixtures can also be carried out by elution on a column packedwith an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

The compounds of the invention can be prepared, for example, using thereaction pathways and techniques as described below.

Compounds of Formula I can be synthesized by those skilled in the art.An example is shown in Scheme 1 (Q isN{(X¹)_(m)(R^(5a))_(n)(X²)_(p)R^(5b)}{Y¹)_(q)(R^(4a))_(r)(Y²)_(s)R^(4b)}and NR′R″ is N(R²){(R^(3a))_(a)(W)_(b)R^(3b)}). Nitriles (1) can beconverted into amide oximes (2). Chlorination of the amide oximes cangive chloro oximes (3) which can be reacted with a variety of amines togive substituted amide oximes (4).

An example synthesis of oxadiazole cores is shown in Scheme 2.4-Amino-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (5) [J.Heterocycl. Chem. (1965), 2, 253] can be converted to the chloro oxime 6[Synth. Commun. (1988), 18, 1427]. The addition of a variety of aminesto 6 can give substituted amide oximes (7).

Additional compounds of Formula I can be synthesized as shown in Scheme3. Protection of amide oxime 7 can give 8 which can be reacted with avariety of alkyl halides, acid halides, sulfonyl halides, isocyanates,and halo formates, etc. (X is a leaving group such as halo), to givetheir respective alkyl amines, amides, sulfonamides, ureas, andcarbamates (9).

Amide oximes can also be prepared as shown in Scheme 4. Coupling of anacid such as 10 with an amine can give amide 11. Amide 11 can beconverted to the thioamide 12 which can be methylated to give the methylthioimidate 13. Reaction of 13 with hydroxylamine can give the amideoxime 14. Alternatively, amide oxime 14 can be formed from thechloroimidate 15 which can be synthesized from amide 11 using phosphoruspentachloride.

Additional amide oximes can be synthesized as described in Scheme 5 (Xis a leaving group). Rearrangement of amide oxime 7 can give 16 whichcan be converted to 17 with sodium nitrite in HCl. Reaction of 17 withamines can give compounds such as 18.

Additional compounds can be synthesized as shown in Scheme 6. Amidecoupling of 8 can give 19 which can be treated with phosphoruspentachloride and subsequently reduced with a hydride such as sodiumcyanoborohydride or borane to give 20. Deprotection of 20 with sodiumhydroxide can give amide oxime 21. Amide 19 can also be deprotected togive 22. Compound 8 can also be converted to 23 which can be coupledwith appropriate alcohols in a Mitsunobu coupling to give 24 afterdeprotection. Alternatively, compound 23 can be alkylated to give 25which can be deprotected to give 26.

Methods of Use

Compounds of the invention can modulate activity of the enzymeindoleamine-2,3-dioxygenase (IDO). The term “modulate” is meant to referto an ability to increase or decrease activity of an enzyme or receptor.Accordingly, compounds of the invention can be used in methods ofmodulating IDO by contacting the enzyme with any one or more of thecompounds or compositions described herein. In some embodiments,compounds of the present invention can act as inhibitors of IDO. Infurther embodiments, the compounds of the invention can be used tomodulate activity of IDO in cell or in an individual in need ofmodulation of the enzyme by administering a modulating (e.g.,inhibiting) amount of a compound of the invention.

The present invention further provides methods of inhibiting thedegradation of tryptophan in a system containing cells expressing IDOsuch as a tissue, living organism, or cell culture. In some embodiments,the present invention provides methods of altering (e.g., increasing)extracellular tryptophan levels in a mammal by administering aneffective amount of a compound of composition provided herein. Methodsof measuring tryptophan levels and tryptophan degradation are routine inthe art.

The present invention further provides methods of inhibitingimmunosuppression such as IDO-mediated immunosuppression in a patient byadministering to the patient an effective amount of a compound orcomposition recited herein. IDO-mediated immunosuppression has beenassociated with, for example, cancers, tumor growth, metastasis, viralinfection, viral replication, etc.

The present invention further provides methods of treating diseasesassociated with activity or expression, including abnormal activityand/or overexpression, of IDO in an individual (e.g., patient) byadministering to the individual in need of such treatment atherapeutically effective amount or dose of a compound of the presentinvention or a pharmaceutical composition thereof. Example diseases caninclude any disease, disorder or condition that is directly orindirectly linked to expression or activity of the IDO enzyme, such asover expression or abnormal activity. An IDO-associated disease can alsoinclude any disease, disorder or condition that can be prevented,ameliorated, or cured by modulating enzyme activity. Examples ofIDO-associated diseases include cancer, viral infection such as HIVinfection, depression, neurodegenerative disorders such as Alzheimer'sdisease and Huntington's disease, trauma, age-related cataracts, organtransplantation (e.g., organ transplant rejection), and autoimmunediseases including asthma, rheumatoid arthritis, multiple sclerosis,inflammatory bowel disease, psoriasis and systemic lupuserythematosusor. Example cancers treatable by the methods herein includecancer of the colon, pancreas, breast, prostate, lung, brain, ovary,cervix, testes, renal, head and neck, lymphoma, leukemia, melanoma, andthe like.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the IDO enzyme with a compound of the inventionincludes the administration of a compound of the present invention to anindividual or patient, such as a human, having IDO, as well as, forexample, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the IDO enzyme.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician, which includes one or more of thefollowing:

(1) preventing the disease; for example, preventing a disease, conditionor disorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease;

(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder; and

(3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

Combination Therapy

One or more additional pharmaceutical agents or treatment methods suchas, for example, anti-viral agents, chemotherapeutics or otheranti-cancer agents, immune enhancers, immunosuppressants, radiation,anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF,etc.), and/or tyrosine kinase inhibitors can be used in combination withthe compounds of the present invention for treatment of IDO-associateddiseases, disorders or conditions. The agents can be combined with thepresent compounds in a single dosage form, or the agents can beadministered simultaneously or sequentially as separate dosage forms.

Suitable antiviral agents contemplated for use in combination with thecompounds of the present invention can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddI);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil[bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Typical suitableprotease inhibitors include saquinavir (Ro 31-8959); ritonavir(ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94);lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549.Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

Suitable chemotherapeutic or other anti-cancer agents include, forexample, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(Cytoxan™) ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Suitable chemotherapeutic or other anti-cancer agents include, forexample, antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors) such as methotrexate, 5-fluorouracil, floxuridine,cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, certain natural products and their derivatives (forexample, vinca alkaloids, antitumor antibiotics, enzymes, lymphokinesand epipodophyllotoxins) such as vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel (Taxol™), mithramycin, deoxyco-formycin,mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide,and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole,letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, anddroloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cis-platin andcarboplatin; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL-10, TGF-β, etc.).

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer.

Anti-cancer vaccines include dendritic cells, synthetic peptides, DNAvaccines and recombinant viruses.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions which is acombination of a compound of the invention and a pharmaceuticallyacceptable carrier. These compositions can be prepared in a manner wellknown in the pharmaceutical art, and can be administered by a variety ofroutes, depending upon whether local or systemic treatment is desiredand upon the area to be treated. Administration may be topical(including ophthalmic and to mucous membranes including intranasal,vaginal and rectal delivery), pulmonary (e.g., by inhalation orinsufflation of powders or aerosols, including by nebulizer;intratracheal, intranasal, epidermal and transdermal), ocular, oral orparenteral. Methods for ocular delivery can include topicaladministration (eye drops), subconjunctival, periocular or intravitrealinjection or introduction by balloon catheter or ophthalmic insertssurgically placed in the conjunctival sac. Parenteral administrationincludes intravenous, intraarterial, subcutaneous, intraperitoneal orintramuscular injection or infusion; or intracranial, e.g., intrathecalor intraventricular, administration. Parenteral administration can be inthe form of a single bolus dose, or may be, for example, by a continuousperfusion pump. Pharmaceutical compositions and formulations for topicaladministration may include transdermal patches, ointments, lotions,creams, gels, drops, suppositories, sprays, liquids and powders.Conventional pharmaceutical carriers, aqueous, powder or oily bases,thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of the inventionabove in combination with one or more pharmaceutically acceptablecarriers. In making the compositions of the invention, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a compound of theinvention in a pharmaceutical composition can vary depending upon anumber of factors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecompounds of the invention can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral administration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

The compounds of the invention can also be formulated in combinationwith one or more additional active ingredients which can include anypharmaceutical agent such as anti-viral agents, vaccines, antibodies,immune enhancers, immune suppressants, anti-inflammatory agents and thelike.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to fluorescent dye, spinlable, heavy metal or radio-labeled compounds of the invention thatwould be useful not only in imaging but also in assays, both in vitroand in vivo, for localizing and quantitating the IDO enzyme in tissuesamples, including human, and for identifying IDO enzyme ligands byinhibition binding of a labeled compound. Accordingly, the presentinvention includes IDO enzyme assays that contain such labeledcompounds.

The present invention further includes isotopically-labeled compounds ofFormula I. An “isotopically” or “radio-labeled” compound is a compoundof the invention where one or more atoms are replaced or substituted byan atom having an atomic mass or mass number different from the atomicmass or mass number typically found in nature (i.e., naturallyoccurring). Suitable radionuclides that may be incorporated in compoundsof the present invention include but are not limited to ²H (also writtenas D for deuterium), ³H (also written as T for tritium), ¹¹C, ¹³C, ¹⁴C,¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I,¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide that is incorporated in theinstant radio-labeled compounds will depend on the specific applicationof that radio-labeled compound. For example, for in vitro IDO enzymelabeling and competition assays, compounds that incorporate ³H, ¹⁴C,⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or will generally be most useful. Forradio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Bror ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art.

A radio-labeled compound of the invention can be used in a screeningassay to identify/evaluate compounds. In general terms, a newlysynthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the radio-labeledcompound of the invention to the IDO enzyme. Accordingly, the ability ofa test compound to compete with the radio-labeled compound for bindingto the IDO enzyme directly correlates to its binding affinity.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of IDO-associated diseases ordisorders, obesity, diabetes and other diseases referred to herein whichinclude one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of theinvention. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results. The example compounds below were found to be inhibitors ofIDO according to one or more of the assays described herein.

EXAMPLES

As detected by ¹H NMR, preparations of the example compounds belowcontained both E and Z isomers. While not wishing to be bound by theory,the major isomer was believed to be the Z isomer based on, for example,the data reported in Zh. Org. Chim. (1993), 29, 1062-1066.

Example 14-Amino-N-(3-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

Step 1. 4-Amino-N-hydroxy-1,2,5-oxadiazole-3-carboximidoyl chloride

A solution of 3 M of hydrogen chloride in water (190 mL) was treatedwith 4-amino-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide [J.Heterocycl. Chem. (1965), 2, 253] (7.3 g, 0.051 mol) at 0° C. Thereaction mixture was treated with enough 12 M hydrogen chloride (˜19 mL)to dissolve the solid and then treated with a solution of sodium nitrite(4.4 g, 0.063 mol) in water (24 mL) dropwise while maintaining aninternal temperature at 0-5° C. with an ice/brine bath. The reactionmixture was stirred at 0° C. for 1.5 h and filtered to yield a beigesolid. Purification of the crude mixture by preparative HPLC gave thedesired product (1.7 g, 21%) as an off-white solid.

Step 2:4-Amino-N-(3-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

A solution of 3-fluoroaniline (36 μL, 0.37 mmol) in ethanol (0.5 mL) wastreated with a solution of4-amino-N-hydroxy-1,2,5-oxadiazole-3-carboximidoyl chloride (50 mg, 0.31mmol) in ethanol (1.5 mL) followed by triethylamine (51 μL, 0.37 mmol)dropwise. The reaction mixture was stirred at 25° C. for 1 h andpurified by preparative LCMS to give the desired product (21 mg, 29%).LCMS for C₉H₉FN₅O₂ (M+H)⁺: m/z=238.0.

Example 2 4-Amino-N′-hydroxy-N-phenyl-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 usinganiline as the starting material. LCMS for C₉H₁₀N₅O₂ (M+H)⁺: m/z=220.0.

Example 34-Amino-N-(2-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using2-chloroaniline as the starting material. LCMS for C₉H₉ClN₅O₂ (M+H)⁺:m/z=254.0.

Example 44-Amino-N-(3-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using3-chloroaniline as the starting material. LCMS for C₉H₉ClN₅O₂ (M+H)⁺:m/z=254.1.

Example 54-Amino-N-(4-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using4-chloroaniline as the starting material. LCMS for C₉H₉ClN₅O₂ (M+H)⁺:m/z=254.1.

Example 64-Amino-N-(4-bromophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using4-bromoaniline as the starting material. LCMS for C₉H₉BrN₅O₂ (M+H)⁺:m/z=297.9.

Example 74-Amino-N′-hydroxy-N-(2-methylphenyl)-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using2-methylaniline as the starting material. LCMS for C₁₀H₁₂N₅O₂ (M+H)⁺:m/z=234.1.

Example 84-Amino-N′-hydroxy-N-(3-methylphenyl)-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using3-methylaniline as the starting material. LCMS for C₁₀H₁₂N₅O₂ (M+H)⁺:m/z=234.0.

Example 94-Amino-N′-hydroxy-N-(4-methylphenyl)-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using4-methylaniline as the starting material. LCMS for C₁₀H₁₂N₅O₂ (M+H)⁺:m/z=234.0.

Example 104-Amino-N′-hydroxy-N-[3-(trifluoromethyl)phenyl]-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using3-(trifluoromethyl)aniline as the starting material. LCMS forC₁₀H₉F₃N₅O₂ (M+H)⁺: m/z=288.0.

Example 114-Amino-N′-hydroxy-N-(2-methoxyphenyl)-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using2-methoxyaniline as the starting material. LCMS for C₁₀H₁₂N₅O₃ (M+H)⁺:m/z=250.0.

Example 124-Amino-N′-hydroxy-N-(3-methoxyphenyl)-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using3-methoxyaniline as the starting material. LCMS for C₁₀H₁₂N₅O₃ (M+H)⁺:=250.0.

Example 13 4-Amino-N′-hydroxy-N-(4-methoxyphenyl)-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using4-methoxyaniline as the starting material. LCMS for C₁₀H₁₂N₅O₃ (M+H)⁺:=250.0.

Example 144-Amino-N-[3-(benzyloxy)phenyl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using3-(benzyloxy)aniline as the starting material. LCMS for C₁₆H₁₆N₅O₃(M+H)⁺: m/z=326.2.

Example 15N-(3-Acetylphenyl)-4-amino-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using3-aminoacetophenone as the starting material. LCMS for C₁₁H₁₂N₅O₃(M+H)⁺: m/z=262.2.

Example 164-Amino-N-(3-cyanophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using3-aminobenzonitrile as the starting material. LCMS for C₁₀H₉N₆O₂ (M+H)⁺:m/z=245.0.

Example 174-Amino-N-(3,4-difluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using3,4-difluoroaniline as the starting material. LCMS for C₉H₈F₂N₅O₂(M+H)⁺: m/z=256.1.

Example 184-Amino-N-(4-bromo-3-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using4-bromo-3-fluoroaniline as the starting material. LCMS for C₉H₈BrFN₅O₂(M+H)⁺: m/z=316.0, 318.0.

Example 194-Amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using3-chloro-4-fluoroaniline as the starting material. LCMS for C₉H₈ClFN₅O₂(M+H)⁺: m/z=272.0.

Example 204-Amino-N-(3-chloro-4-methylphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using3-chloro-4-methylaniline as the starting material. LCMS for C₁₀H₁₁ClN₅O₂(M+H)⁺: m/z=268.1.

Example 214-Amino-N-(3,4-dimethylphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using3,4-dimethylaniline as the starting material. LCMS for C₁₁H₁₄N₅O₂(M+H)⁺: m/z=248.0.

Example 224-Amino-N-[4-(benzyloxy)-3-chlorophenyl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using4-(benzyloxy)-3-chloroaniline as the starting material. LCMS forC₁₆H₁₅ClN₅O₃ (M+H)⁺: m/z=360.0.

Example 234-Amino-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using4-fluoro-3-(trifluoromethyl)aniline as the starting material. LCMS forC₁₀H₈F₄N₅O₂ (M+H)⁺: m/z=306.1.

Example 244-Amino-N-benzyl-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 usingbenzylamine as the starting material. LCMS for C₁₀H₁₂N₅O₂ (M+H)⁺:m/z=234.2.

Example 254-Amino-N-(2-fluorobenzyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using2-fluorobenzylamine as the starting material. LCMS for C₁₀H₁₁FN₅O₂(M+H)⁺: m/z=252.0.

Example 264-Amino-N-(2-chlorobenzyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using2-chlorobenzylamine as the starting material. LCMS for C₁₀H₁₁ClN₅O₂(M+H)⁺: m/z=268.1.

Example 274-Amino-N-(3-chlorobenzyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using3-chlorobenzylamine as the starting material. LCMS for C₁₀H₁₁ClN₅O₂(M+H)⁺: m/z=268.0.

Example 284-Amino-N-(4-chlorobenzyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using4-chlorobenzylamine as the starting material. LCMS for C₁₀H₁₁ClN₅O₂(M+H)⁺: m/z=268.1.

Example 294-Amino-N′-hydroxy-N-[3-(trifluoromethyl)benzyl]-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using3-(trifluoromethyl)benzylamine as the starting material. LCMS forC₁₁H₁₁F₃N₅O₂ (M+H)⁺: m/z=302.2.

Example 30 4-Amino-N′-hydroxy-N-(2-methoxybenzyl)-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using2-(methoxy)benzylamine as the starting material. LCMS for C₁₁H₁₄N₅O₃(M+H)⁺: m/z=264.0.

Example 314-Amino-N′-hydroxy-N-(pyridin-2-ylmethyl)-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using2-(aminomethyl)pyridine as the starting material. LCMS for C₉H₁₁N₆O₂(M+H)⁺: m/z=235.0.

Example 324-Amino-N′-hydroxy-N-(2-phenylethyl)-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 usingphenethylamine as the starting material. LCMS for C₁₁H₁₄N₅O₂ (M+H)⁺:m/z=248.0.

Example 334-Amino-N′-hydroxy-N-1H-indol-5-yl-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 using5-aminoindole as the starting material. LCMS for C₁₁H₁₁N₆O₂ (M+H)⁺:m/z=259.2.

Example 34 4-Amino-N-butyl-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 1 usingbutylamine as the starting material. LCMS for C₇H₁₄N₅O₂ (M+H)⁺:m/z=200.2.

Example 35N-{4-[[(3-Chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-phenylacetamide

Step 1:3-(4-Amino-1,2,5-oxadiazol-3-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one

A solution of4-amino-N-(3-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide(540 mg, 2.1 mmol) and N,N-carbonyldiimidazole (380 mg, 2.3 mmol) intetrahydrofuran (10 mL) was heated at 80° C. for 1 h. The reactionmixture was diluted with ethyl acetate (150 mL) and washed with 0.1 NHCl (3×75 mL) and brine (75 mL). The organic layer was dried with sodiumsulfate, filtered, and concentrated to give the desired product (560 mg,94%) as a white solid which was used without further purification. LCMSfor C₁₀H₇ClN₅O₃ (M+H)⁺: m/z=279.9.

Step 2:N-{4-[[(3-Chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-phenylacetamide

A solution of3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one(30.0 mg, 0.107 mmol) and 4-dimethylaminopyridine (2.6 mg, 0.021 mmol)in pyridine (0.50 mL) was treated with benzeneacetyl chloride (42.6 μL,0.322 mmol) and stirred for 4 h. The reaction mixture was concentratedand rediluted with ethanol (1.0 mL) and 2 M of sodium hydroxide in water(0.30 mL) stirred for 45 min. Purification of the crude reaction mixtureby preparative HPLC gave the desired product (18 mg, 45%). LCMS forC₁₇H₁₅ClN₅O₃ (M+H)⁺: m/z=371.9.

Example 36N-{4-[[(3-Chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}benzamide

This compound was prepared according to the procedure of Example 35using benzoyl chloride as the starting material. LCMS for C₁₆H₁₃ClN₅O₃(M+H)⁺: m/z=358.1.

Example 37N-{4-[(Benzylamino)(hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}benzamide

This compound was prepared according to the procedure of Example 35using3-(4-amino-1,2,5-oxadiazol-3-yl)-4-benzyl-1,2,4-oxadiazol-5(4H)-one andbenzoyl chloride as the starting materials. LCMS for C₁₇H₁₆N₅O₃ (M+H)⁺:m/z=338.2.

Example 38N-benzyl-4-(benzylamino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

Step 1.4-Benzyl-3-[4-(benzylamino)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-one

A solution of3-(4-amino-1,2,5-oxadiazol-3-yl)-4-benzyl-1,2,4-oxadiazol-5(4H)-one(60.0 mg, 0.231 mmol) and benzyl bromide (28 μL, 0.23 mmol) was heatedat 150° C. for 5 h. Additional benzyl bromide (28 μL) was added to theincomplete reaction and heating was continued for another 16 h.Purification of the crude reaction mixture by preparative HPLC gave thedesired product (12 mg, 15%). LCMS for C₁₈H₁₆N₅O₃ (M+H)⁺: m/z=349.9.

Step 2.N-benzyl-4-(benzylamino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

A solution of4-benzyl-3-[4-(benzylamino)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-one(12 mg, 34 μmol) in ethanol (1 mL) was treated with 2 M sodium hydroxidein water (300 μL) and stirred at 25° C. for 30 min. The reaction mixturewas quenched with acetic acid and purified by preparative HPLC to givethe desired product (10 mg, 90%) as a white solid. LCMS for C₁₇H₁₈N₅O₂(M+H)⁺: m/z=324.2.

Example 394-[(Anilinocarbonyl)amino]-N-(3-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

Example 404-[Bis(anilinocarbonyl)amino]-N-(3-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

Step 1.N-{4-[4-(3-Chlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-N′-phenylureaandN-{4-[4-(3-chlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-N,N′-diphenyldicarbonimidicdiamide

A solution of3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one(30 mg, 0.1 mmol) in pyridine (0.5 mL, 6.2 mmol) was treated with phenylisocyanate (12 μL, 0.1 mmol) and stirred for 2 h. The reaction mixturewas treated with 4-dimethylaminopyridine (3 mg, 24 wimp and additionalphenyl isocyanate (10 μL, 92 μmol) and stirred for another 2 h.Purification of the crude reaction mixture by preparative HPLC gave thedesired productsN-{4-[4-(3-chlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-N′-phenylurea(5 mg, 12%) andN-{4-[4-(3-chlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-N,N′-diphenyldicarbonimidicdiamide (7 mg, 12%). LCMS for C₁₇H₁₂ClN₆O₄ (M+H)⁺: m/z=398.9 and LCMSfor C₂₄H₁₆ClN₇O₅Na (M+H)⁺: m/z=540.0.

Step 2.4-[(Anilinocarbonyl)amino]-N-(3-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamideand4-[Bis(anilinocarbonyl)amino]-N-(3-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

A solution ofN-{4-[4-(3-chlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-N′-phenylurea(17 mg, 43 μmol) in ethanol (1.5 mL) was treated with 2.0 M sodiumhydroxide in water (0.3 mL) and stirred for 30 min. Purification of thecrude reaction mixture by preparative HPLC gave the desired product4-[(anilinocarbonyl)amino]-N-(3-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide(6 mg, 38%). LCMS for C₁₆H₁₄ClN₆O₃ (M+H)⁺: m/z=373.0.

4-[Bis(anilinocarbonyl)amino]-N-(3-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamidewas prepared in a similar fashion fromN-{4-[4-(3-chlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-N,N′-diphenyldicarbonimidicdiamide. LCMS for C₂₃H₁₉ClN₇O₄ (M+H)⁺: m/z=492.0.

Example 41 tert-Butyl{4-[({4-[(E,Z)-[(3-chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}amino)carbonyl]benzyl}carbamate

Step 1. tert-Butyl{4-[({4-[4-(3-chlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)carbonyl]benzyl}carbamate

A solution of3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one(50 mg, 0.18 mmol) and 4-{[(tert-butoxycarbonyl)amino]methyl}benzoicacid (49 mg, 0.2 mmol) in dichloromethane (3.5 mL) was treated with4-dimethylaminopyridine (13 mg, 0.1 mmol) and N,N-diisopropylethylamine(93 μL, 0.54 mmol). After the reaction mixture turned clear, it wastreated with bromotris(pyrrolydino)phosphonium hexafluorophosphate (50mg, 0.11 mmol) and additional N,N-diisopropylethylamine (93 μL, 0.54mmol). The reaction mixture was stirred for 16 h, treated withadditional bromotris(pyrrolydino)phosphonium hexafluorophosphate (50 mg,0.11 mmol), and stirred for another 6 h. The reaction mixture wasdiluted with ethyl acetate (60 mL) and washed with 0.1 M HCl (2×25 mL)and brine (25 mL), dried with sodium sulfate, filtered, andconcentrated. Purification of the crude reaction mixture by preparativeLCMS gave the desired product (22 mg, 24%).

LCMS for C₁₉H₁₄ClN₆O₆ ([M-tBu+H]+H)⁺: m/z=457.1.

Step 2. tert-Butyl{-[({4-[(E,Z)-[(3-chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}amino)carbonyl]benzyl}carbamate

This compound was prepared according to the procedure of Example 38,Step 2, using tert-butyl{4-[({4-[4-(3-chlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)carbonyl]benzyl}carbamateas the starting material. LCMS for C₂₂H₂₄ClN₆O₅ (M+H)⁺: m/z=487.0.

Example 424-(Aminomethyl)-N-{4-[(E,Z)-[(3-chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}benzamidetrifluoroacetate

Step 1.4-(Aminomethyl)-N-{4-[4-(3-chlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}benzamidetrifluoroacetate

A solution of3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one(0.5 g, 1.8 mmol) and 4-{[(tert-butoxycarbonyl)amino]methyl}benzoic acid(0.67 g, 2.7 mmol) in dichloromethane (35 mL) was treated with4-dimethylaminopyridine (0.13 g, 1.1 mmol) and N,N-diisopropylethylamine(0.93 mL, 5.4 mmol) followed by bromotris(pyrrolydino)phosphoniumhexafluorophosphate (1.3 g, 2.7 mmol) and additionalN,N-diisopropylethylamine (0.93 mL, 5.4 mmol). The reaction mixture wasstirred for 16 h, diluted with ethyl acetate (˜200 mL) and washed with0.1 M HCl (2×100 mL) and brine (25 mL), dried with sodium sulfate,filtered, and concentrated. Purification of the crude reaction mixtureon silica gel gave the intermediate tert-butyl{4-[({4-[4-(3-chlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)carbonyl]benzyl}carbamate.This material was diluted with dichloromethane (30 mL), treated with 4.0M HCl in 1,4-dioxane (4.5 mL), and stirred for 1 h. The reaction mixturewas concentrated and purified by preparative LCMS to give the desiredproduct (542 mg, 58%). LCMS for C₁₈H₁₄ClN₆O₄ (M+H)⁺: m/z=413.0.

Step 2.4-(Aminomethyl)-N-{4-[(E,Z)-[(3-chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}benzamidetrifluoroacetate

This compound was prepared according to the procedure of Example 38,Step 2, using4-(aminomethyl)-N-{4-[4-(3-chlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}benzamidetrifluoroacetate as the starting material. LCMS for C₁₇H₁₆ClN₆O₃ (M+H)⁺:m/z=387.0.

Example 434-{[(Benzylamino)carbonyl]amino}-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

A solution of3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one(30 mg, 88 μmol) and 4-dimethylaminopyridine (5 mg, 40 μmol) in pyridine(0.5 mL) was treated with benzyl isocyanate (29 mg, 0.2 mmol) and heatedin the microwave at 150° C. for 20 min. The reaction mixture wasconcentrated and purified by preparative LCMS to give the intermediateN-benzyl-N′-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}urea.This material was diluted with ethanol (1.5 mL), treated with 2.0 Msodium hydroxide in water (0.3 mL), and stirred for 30 min. Purificationof the crude reaction mixture by preparative HPLC gave the desiredproduct (11 mg, 28%). LCMS for C₁₇H₁₅BrFN₆O₃ (M+H)⁺: m/z=448.9, 451.0.

Example 444-Amino-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-thiadiazole-3-carboximidamide

Step 1.4-Amino-N-(3-bromo-4-fluorophenyl)-1,2,5-thiadiazole-3-carboxamide

A solution of 4-amino-1,2,5-thiadiazole-3-carboxylic acid (250 mg, 1.7mmol) and 3-bromo-4-fluoroaniline (393 mg, 2.1 mmol) inN,N-dimethylformamide (5 mL) was treated withO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(784 mg, 2.1 mmol) followed by N,N-diisopropylethylamine (0.36 mL, 2.1mmol) and stirred for 16 h. The reaction mixture was diluted with brine(50 mL) and 0.1 N HCl (100 mL) and extracted with ethyl acetate (2×150mL). The combined organic extracts were washed with brine (50 mL), driedwith sodium sulfate, filtered, and concentrated. Purification of thecrude reaction mixture on silica gel gave the desired product (414 mg,76%). LCMS for C₉H₇BrFN₄OS(M+H)⁺: m/z=316.9, 318.8.

Step 2.4-Amino-N-(3-bromo-4-fluorophenyl)-1,2,5-thiadiazole-3-carbothioamide

A solution of4-amino-N-(3-bromo-4-fluorophenyl)-1,2,5-thiadiazole-3-carboxamide (225mg, 0.7 mmol) and2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (570mg, 1.4 mmol) in toluene (6.8 mL) was stirred at 95° C. for 16 h. Thereaction mixture was diluted with ethyl acetate (50 mL) and theinsoluble salts were filtered. The filtrate was concentrated to a cruderesidue which was purified on silica gel to give the desired product(130 mg, 55%). LCMS for C₉H₇BrFN₄S₂ (M+H)⁺: m/z=332.8, 334.9.

Step 3. Methyl4-amino-N-(3-bromo-4-fluorophenyl)-1,2,5-thiadiazole-3-carbimidothioate

A solution of4-amino-N-(3-bromo-4-fluorophenyl)-1,2,5-thiadiazole-3-carbothioamide(130 mg, 0.4 mmol) in dichloromethane (5.2 mL) was treated with methyltrifluoromethanesulfonate (64 μL, 0.6 mmol) followed byN,N-diisopropylethylamine (102 μL, 0.6 mmol) and stirred for 1 h. Thereaction mixture was diluted with dichloromethane (100 mL), washed withwater (50 mL) and brine (50 mL), dried with sodium sulfate, filtered,and concentrated to give the desired product (133 mg, 98%). LCMS forC₁₀H₉BrFN₄S₂ (M+H)⁺: m/z=346.8, 348.8.

Step 4.4-Amino-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-thiadiazole-3-carboximidamide

A solution of methyl4-amino-N-(3-bromo-4-fluorophenyl)-1,2,5-thiadiazole-3-carbimidothioate(78 mg, 0.22 mmol) in ethanol (2.3 mL) was treated with hydroxylaminehydrochloride (62 mg, 0.9 mmol) followed by N,N-diisopropylethylamine(180 μL, 1.0 mmol) and stirred at 90° C. for 16 h. The reaction mixturewas purified by preparative HPLC to give the desired product (58 mg,78%). LCMS for C₉H₈BrFN₅OS (M+H)⁺: m/z=331.9, 333.9.

Example 454-Amino-N-(6-chloropyridin-2-yl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamidetrifluoroacetate

Step 1. 4-Amino-N-(6-chloropyridin-2-yl)-1,2,5-oxadiazole-3-carboxamide

A solution of 4-amino-1,2,5-oxadiazole-3-carboxylic acid (0.4 g, 3.1mmol) and 6-chloropyridin-2-amine (0.56 g, 4.3 mmol) inN,N-dimethylformamide (6.2 mL) was treated withN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (1.4 g, 3.7 mmol) followed byN,N-diisopropylethylamine (0.76 mL, 4.3 mmol) at 0° C. The reactionmixture was stirred at 25° C. for 2 h, poured into saturated NaHCO₃ (50mL) and extracted with ethyl acetate (100 mL). The organic layer wasseparated and washed with brine (25 mL), dried with sodium sulfate,filtered, and concentrated to a crude solid. The crude solid was washedwith ethyl acetate and filtered. The filtrate was concentrated andpurified on silica gel to give the desired product with some impurities.The impurities were removed by washing the solid with chloroform toyield the desired product (65 mg, 9%). LCMS for C₈H₇ClN₅O₂ (M+H)⁺:m/z=240.1.

Step 2.4-Amino-N-(6-chloropyridin-2-yl)-1,2,5-oxadiazole-3-carboximidoylchloride

A solution of4-amino-N-(6-chloropyridin-2-yl)-1,2,5-oxadiazole-3-carboxamide (62 mg,0.26 mmol) in benzene (5 mL) was treated with phosphorus pentachloride(0.12 g, 0.57 mmol) and stirred at reflux for 3 h. The reaction mixturewas concentrated and rediluted with benzene and concentrated (3×) togive the desired product which was used immediately in the next step.

Step 3.4-Amino-N-(6-chloropyridin-2-yl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamidetrifluoroacetate

A solution of4-amino-N-(6-chloropyridin-2-yl)-1,2,5-oxadiazole-3-carboximidoylchloride (67 mg, 0.26 mmol) in tetrahydrofuran (3 mL) was treated with20 M hydroxylamine in water (0.26 mL, 5 mmol) and stirred at 60° C. for4 h. The reaction mixture was treated with additional 20 M hydroxylaminein water (0.13 mL, 2.5 mmol) and heated at 70° C. for 1.5 h. Thereaction mixture was concentrated to a crude residue which was purifiedby preparative LCMS to give the desired product (12 mg, 12%). LCMS forC₈H₈ClN₆O₂ (M+H)⁺: m/z=255.0.

Example 464-Amino-N-(3-bromo-4-fluorophenyl)-N′-hydroxyisothiazole-3-carboximidamidetrifluoroacetate

Step 1. 4-Amino-N-(3-bromo-4-fluorophenyl)isothiazole-3-carboxamide

This compound was prepared according to the procedure of Example 44,Step 1, using 4-aminoisothiazole-3-carboxylic acid hydrochloride and3-bromo-4-fluoroaniline as the starting materials. LCMS for C₁₀H₈BrFN₃OS(M+H)⁺: m/z=315.9, 317.9.

Step 2. 4-Amino-N-(3-bromo-4-fluorophenyl)isothiazole-3-carboximidoylchloride

This compound was prepared according to the procedure of Example 45,Step 2, using4-amino-N-(3-bromo-4-fluorophenyl)isothiazole-3-carboxamide as thestarting material and was used immediately in the next step.

Step 3.4-Amino-N-(3-bromo-4-fluorophenyl)-N′-hydroxyisothiazole-3-carboximidamidetrifluoroacetate

This compound was prepared according to the procedure of Example 45,Step 3, using4-amino-N-(3-bromo-4-fluorophenyl)isothiazole-3-carboximidoyl chlorideas the starting material. LCMS for C₁₀H₉BrFN₄OS (M+H)⁺: m/z=330.9,332.9.

Example 474-Amino-N-(2,5-dichlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

Step 1. 4-Amino-N-(2,5-dichlorophenyl)-1,2,5-oxadiazole-3-carboxamide

This compound was prepared according to the procedure of Example 45,Step 1, using 4-amino-1,2,5-oxadiazole-3-carboxylic acid and2,5-dichloroaniline as the starting materials. LCMS for C₉H₇Cl₂N₄O₂(M+H)⁺: m/z=273.0.

Step 2. 4-Amino-N-(2,5-dichlorophenyl)-1,2,5-oxadiazole-3-carbothioamide

This compound was prepared according to the procedure of Example 44,Step 2, using4-amino-N-(2,5-dichlorophenyl)-1,2,5-oxadiazole-3-carboxamide as thestarting material. LCMS for C₉H₇Cl₂N₄OS (M+H)⁺: m/z=289.0.

Step 3. Methyl4-amino-N-(2,5-dichlorophenyl)-1,2,5-oxadiazole-3-carbimidothioate

This compound was prepared according to the procedure of Example 44,Step 3, using4-amino-N-(2,5-dichlorophenyl)-1,2,5-oxadiazole-3-carbothioamide as thestarting material and was used immediately in the next step.

Step 4.4-Amino-N-(2,5-dichlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 44,Step 4, using methyl4-amino-N-(2,5-dichlorophenyl)-1,2,5-oxadiazole-3-carbimidothioate asthe starting material. LCMS for C₉H₈Cl₂N₅O₂ (M+H)⁺: m/z=288.0.

Example 48N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}morpholine-4-carboxamide

Step 1. Phenyl{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}carbamate

This compound was prepared according to the procedure of Example 35using3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-oneand phenyl chloroformate as the starting materials. LCMS forC₁₇H₁₀BrFN₅O₅ (M+H)⁺: m/z=461.9, 463.7.

Step 2.N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}morpholine-4-carboxamide

A solution of phenyl{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}carbamate(25 mg, 54 μmol) in dichloromethane (1 mL) was treated with morpholine(14 μL, 0.16 mmol) and stirred for 2 h. The reaction mixture wasconcentrated to a crude residue which was diluted with ethanol (1 mL),treated with 2.0 M sodium hydroxide in water (0.15 mL, 3 mmol), andstirred for 45 min. The reaction mixture was purified by preparativeHPLC to give the desired product (6 mg, 26%). LCMS for C₁₄H₁₅BrFN₆O₄(M+H)⁺: m/z=428.9, 430.9.

Example 49N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-(methylamino)-1,2,5-oxadiazole-3-carboximidamide

Step 1.N-{4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-2,2,2-trifluoroacetamide

A solution of3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one(0.4 g, 1.2 mmol) in pyridine (6.5 mL) was treated with4-dimethylaminopyridine (71 mg, 0.6 mmol) and trifluoroacetic anhydride(0.41 mL, 2.9 mmol) and stirred for 20 min. The reaction mixture wasconcentrated to a crude residue which was purified by silica gel to givethe desired product (0.46 g, 89%). LCMS for C₁₂H₅BrF₄N₅O₄ (M+H)⁺:m/z=438.0, 439.9.

Step 2.4-(3-Bromo-4-fluorophenyl)-3-[4-(methylamino)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-one

A solution ofN-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-2,2,2-trifluoroacetamide(0.59 mg, 1.3 mmol) in N,N-dimethylformamide (3 mL) was treated withpotassium carbonate (0.28 g, 2.0 mmol) followed by methyl iodide (125μL, 2 mmol) and stirred for 2 h. The reaction mixture was treated withadditional methyl iodide (200 μL, 3.2 mmol) and stirred for 16 h. Thereaction mixture was diluted with water (100 mL) and brine (25 mL) andextracted with ethyl acetate (2×100 mL). The combined organic extractswere washed with water (3×100 mL) and brine (100 mL), dried with sodiumsulfate, filtered, and concentrated to a crude residue which waspurified by silica gel to give the desired product (0.39 g, 81%).

LCMS for C₁₁H₈BrFN₅O₃ (M+H)⁺: m/z=355.9, 358.0.

Step 3.N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-(methylamino)-1,2,5-oxadiazole-3-carboximidamide

This compound was prepared according to the procedure of Example 38,Step 2, using4-(3-bromo-4-fluorophenyl)-3-[4-(methylamino)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-oneas the starting material. LCMS for C₁₀H₁₀BrFN₅O₂ (M+H)⁺: m/z=329.9,332.0.

Example 50N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}piperidine-4-carboxamidetrifluoroacetate

Step 1.N-{4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-1-(trifluoroacetyl)piperidine-4-carboxamide

This compound was prepared according to the procedure of Example 35using3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-oneand 1-(trifluoroacetyl)piperidine-4-carbonyl chloride as the startingmaterials. LCMS for C₁₈H₁₄BrF₄N₆O₅ (M+H)⁺: m/z=549.0, 550.9.

Step 2.N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}piperidine-4-carboxamidetrifluoroacetate

This compound was prepared according to the procedure of Example 38,Step 2, usingN-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-1-(trifluoroacetyl)piperidine-4-carboxamideas the starting material. LCMS for C₁₅H₁₇BrFN₆O₃ (M+H)⁺: m/z=427.0,429.9.

Example 51 tert-Butyl4-{4-[({4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}amino)carbonyl]benzyl}piperazine-1-carboxylatetrifluoroacetate

A solution of3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one(30 mg, 88 μmol),4-{[4-(tert-butoxycarbonyl)piperazin-1-yl]methyl}benzoic acid (84 mg,0.26 mmol), and 4-dimethylaminopyridine (6.4 mg, 53 μmol) in pyridine(0.75 mL) was treated with phosphoryl chloride (25 μL, 0.27 mmol)dropwise at −15° C. The reaction mixture was heated in a microwave at100° C. for 5 min. The reaction mixture was concentrated to residuewhich was rediluted with methanol (1 mL), treated with 2.0 M sodiumhydroxide in water (0.3 mL, 0.6 mmol), and stirred for 30 min. Thereaction mixture was quenched with acetic acid (50 μL, 0.9 mmol),filtered, and purified by preparative LCMS to give the desired product(29 mg, 45%). LCMS for C₂₆H₃₀BrFN₇O₅ (M+H)⁺: m/z=618.0, 620.0.

Example 52N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-(piperazin-1-ylmethyl)benzamidebis(trifluoroacetate)

A solution of tert-butyl4-{4-[({4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino]-(hydroxyimino)-methyl]-1,2,5-oxadiazol-3-yl}amino)carbonyl]-benzyl}piperazine-1-carboxylatetrifluoroacetate (25 mg, 34 μmol) in dichloromethane (2 mL) was treatedwith 4.0 M HCl in 1,4-dioxane (1 mL), and stirred for 1 h. The reactionmixture was concentrated and purified by preparative HPLC to give thedesired product (15 mg, 59%). LCMS for C₂₁H₂₂BrFN₇O₃ (M+H)⁺: m/z=518.0,520.0.

Example 531-Benzoyl-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}piperidine-4-carboxamide

This compound was prepared according to the procedure of Example 35,Step 2, usingN-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}piperidine-4-carboxamidetrifluoroacetate and benzoyl chloride as the starting materials. LCMSfor C₂₂H₂₁BrFN₆O₄ (M+H)⁺: m/z=531.0, 5310.

Example 54N(4)-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-N(1)-phenylpiperidine-1,4-dicarboxamide

A solution ofN-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}piperidine-4-carboxamidetrifluoroacetate (20 mg, 35 μmol) and 4-dimethylaminopyridine (2 mg, 20μmol) in acetonitrile (0.13 mL) was treated with phenyl isocyante andstirred for 16 h. The reaction mixture was concentrated, rediluted withethanol (0.4 mL), treated with 2.0 M sodium hydroxide in water (0.12 mL,0.24 mmol), and stirred for 30 min. The reaction mixture was quenchedwith acetic acid (20 μL, 0.35 mmol), filtered, and purified bypreparative HPLC to give the desired product (6 mg, 31%). LCMS forC₂₂H₂₂BrFN₇O₄ (M+H)⁺: m/z=546.0, 548.0.

Example 55N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1-ethylpiperidine-4-carboxamidetrifluoroacetate

A solution ofN-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}piperidine-4-carboxamidetrifluoroacetate (20 mg, 35 μmol) in acetonitrile (1 mL) was treatedwith N,N-diisopropylethylamine (12 μL, 71 μmol) followed by iodoethane(4 μL, 53 μmol) and stirred for 16 h. The reaction mixture wasconcentrated, rediluted with ethanol (1 mL), treated with 2.0 M sodiumhydroxide in water (0.2 mL, 0.4 mmol), and stirred for 30 min. Thereaction mixture was quenched with acetic acid (50 μL, 0.88 mmol),filtered, and purified by preparative HPLC to give the desired product(5 mg, 25%). LCMS for C₁₇H₂₁BrFN₆O₃ (M+H)⁺: m/z=455.0, 457.0.

Example 564-[(Benzoylamino)methyl]-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}benzamide

A solution of4-(aminomethyl)-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino]-(hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}benzamidetrifluoroacetate (30 mg, 51 μmol) and benzoic acid (9.3 mg, 76 μmol) indichloromethane (0.4 mL) and N,N-dimethylformamide (0.1 mL) was treatedwith N,N-diisopropylethylamine (22 μL, 0.1 mmol) and 0.6 M of1-hydroxy-7-azabenzotriazole in N,N-dimethylformamide (20 μL, 10 μmol)followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(14.5 mg, 76 μmol) and stirred for 16 h. The reaction mixture wasconcentrated, rediluted with ethanol (1 mL), treated with 2.0 M sodiumhydroxide in water (0.3 mL, 0.6 mmol), and stirred for 30 min. Thereaction mixture was quenched with acetic acid (50 μL, 0.88 mmol),filtered, and purified by preparative HPLC to give the desired product(4 mg, 14%). LCMS for C₂₄H₁₉BrFN₆O₄ (M+H)⁺: m/z=553.0, 555.0.

Example 57N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(2-cyanophenoxy)acetamide

A solution of (2-cyanophenoxy)acetic acid (62 mg, 0.35 mmol) indichloromethane (3 mL) was treated with oxalyl chloride (60 μL, 0.7mmol) followed by N,N-dimethylformamide (10 μL) at 0° C. The reactionmixture was stirred at 25° C. for 2 h and concentrated to a cruderesidue which was diluted with pyridine and treated with3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one(40 mg, 0.12 mmol) and 4-dimethylaminopyridine (7 mg, 58 μmol). Thereaction mixture was heated in the microwave at 150° C. for 20 min. Thereaction mixture was concentrated, rediluted with ethanol (1.45 mL),treated with 2.0 M sodium hydroxide in water (0.3 mL, 0.6 mmol), andstirred for 30 min. The reaction mixture was quenched with acetic acid(50 μL, 0.88 mmol), filtered, and purified by preparative LCMS to givethe desired product (4 mg, 7%). LCMS for C₁₈H₁₃BrFN₆O₄ (M+H)⁺:m/z=474.9, 477.0.

Example 58N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-phenylpiperidine-4-carboxamidetrifluoroacetate

Step 1.N-{4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-4-phenylpiperidine-4-carboxamidetrifluoroacetate

A solution of3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one(0.15 g, 0.44 mmol),1-(tert-butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid (0.4 g, 1.3mmol), and 4-dimethylaminopyridine (32 mg, 0.26 mmol) in acetonitrile (2mL) was treated with phosphoryl chloride (0.13 mL, 1.4 mmol) and heatedin the microwave at 100° C. for 10 min. The reaction mixture wasconcentrated and the residue was diluted with ethyl acetate (25 mL) andwashed with water (25 mL) and brine (25 mL), dried with sodium sulfate,filtered, and concentrated to a crude residue which was purified bysilica gel to give the coupled product, tert-butyl4-[({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)carbonyl]-4-phenylpiperidine-1-carboxylate.This material was diluted with dichloromethane (5 mL) and treated with4.0 M HCl in 1,4-dioxane (3 mL) and stirred for 45 min. The reactionmixture was concentrated and the crude residue was purified bypreparative LCMS to give the desired product (10 mg, 4%). LCMS forC₂₂H₁₉BrFN₆O₄ (M+H)⁺: m/z=529.0, 531.0.

Step 2.N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-phenylpiperidine-4-carboxamidetrifluoroacetate

This compound was prepared according to the procedure of Example 38,Step 2, usingN-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-4-phenylpiperidine-4-carboxamidetrifluoroacetate as the starting material. LCMS for C₂₁H₂₁BrFN₆O₃(M+H)⁺: m/z=503.0, 504.9.

Example 59N-(3-Bromo-4-fluorophenyl)-4-({4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzyl}amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamidetrifluoroacetate

Step 1.N-{4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzamidetrifluoroacetate

A solution of3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one(0.50 g, 1.5 mmol), 4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzoicacid (1.0 g, 3.7 mmol), and 4-dimethylaminopyridine (110 mg, 0.88 mmol)in acetonitrile (8.3 mL) and pyridine (1.2 mL) was treated withphosphoryl chloride (0.42 mL, 4.5 mmol) dropwise at 0° C. The reactionmixture was heated in the microwave at 120° C. for 20 min., diluted withethyl acetate (150 mL) and washed with water (50 mL), saturated sodiumbicarbonate (50 mL), and brine (50 mL), dried with sodium sulfate,filtered, and concentrated. Purification of the crude reaction mixtureby preparative LCMS gave the desired product (0.36 g, 35%). LCMS forC₂₂H₁₉BrFN₆O₆S (M+H)⁺: m/z=593.0, 595.0.

Step 2.N-(3-Bromo-4-fluorophenyl)-4-({4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzyl}amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamidetrifluoroacetate

A solution ofN-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-4-[(1,1-dioxidothiomorpholin-4-yl)methyl]-benzamidetrifluoroacetate (20 mg, 28 μmol) in tetrahydrofuran (0.83 mL) wastreated with 2.0 M of borane-dimethyl sulfide complex in toluene (42 μL,85 μmol) was heated in the microwave at 130° C. for 5 min. The reactionmixture was treated with additional 2.0 M of borane-dimethyl sulfidecomplex in toluene (40 μL, 80 μmol) and heated in the microwave at 130°C. for 10 min. The reaction mixture was quenched with acetic acid,concentrated and purified by preparative LCMS to give the desiredproduct (1 mg, 5%). LCMS for C₂₁H₂₃BrFN₆O₄S (M+H)⁺: m/z=553.0, 554.9.

Example 60N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-{[4-(morpholin-4-ylmethyl)benzyl]amino}-1,2,5-oxadiazole-3-carboximidamidetrifluoroacetate

Step 1.N-{4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-4-(morpholin-4-ylmethyl)benzamidetrifluoroacetate

This compound was prepared according to the procedure of Example 59,Step 1, using 4-(morpholin-4-ylmethyl)benzoic acid as the startingmaterial. LCMS for C₂₂H₁₉BrFN₆O₅ (M+H)⁺: m/z=544.9, 547.0.

Step 2.N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-{[4-(morpholin-4-ylmethyl)benzyl]amino}-1,2,5-oxadiazole-3-carboximidamidetrifluoroacetate

A solution ofN-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-4-(morpholin-4-ylmethyl)benzamidetrifluoroacetate (60 mg, 91 μmol) in benzene (1.8 mL) was treated withphosphorus pentachloride (76 mg, 0.36 mmol) and stirred at reflux for2.5 h. The reaction mixture was concentrated to a residue which wasdiluted with ethanol (1.4 mL), treated with sodium cyanoborohydride (17mg, 0.27 mmol), and stirred for 2 h. The reaction mixture was quenchedwith acetic acid (50 μL) and purified by preparative LCMS to give theintermediate,4-(3-bromo-4-fluorophenyl)-3-(4-{[4-(morpholin-4-ylmethyl)benzyl]amino}-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one.This material was diluted with ethanol (1 mL), treated with 2.0 M sodiumhydroxide in water (0.2 mL, 4 mmol), and stirred for 45 min. Thereaction mixture was purified by preparative LCMS to give the desiredproduct (15 mg, 27%). LCMS for C₂₁H₂₃BrFN₆O₃ (M+H)⁺: m/z=505.0, 507.0.

Example 61N-(3-Cyano-4-fluorophenyl)-4-({4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzyl}amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamidetrifluoroacetate

Step 1.4-(3-Bromo-4-fluorophenyl)-3-[4-({4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzyl}amino)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-onetrifluoroacetate

A solution ofN-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzamidetrifluoroacetate (20 mg, 28 μmol) in pyridine (0.5 mL) was treated withphosphorus pentachloride (18 mg, 85 μmol) and stirred at 0° C. for 4.5h. The reaction mixture was concentrated, diluted with ethanol (1 mL),treated with sodium cyanoborohydride (5 mg, 85 mop, and stirred for 2 h.The reaction mixture was purified by preparative LCMS to give thedesired product (9 mg, 47%). LCMS for C₂₂H₂₁BrFN₆O₅S (M+H)⁺: m/z=579.0,581.0.

Step 2.N-(3-Cyano-4-fluorophenyl)-4-({4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzyl}amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamidetrifluoroacetate

A solution of4-(3-bromo-4-fluorophenyl)-3-[4-({4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzyl}amino)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-onetrifluoroacetate (10 mg, 14 μmol), zinc cyanide (5 mg, 43 mmol), andtetrakis(triphenylphosphine)palladium(0) (8 mg, 7 μmol) inN,N-dimethylformamide (0.25 mL) was heated in the microwave at 150° C.for 5 min. The reaction mixture was diluted with 3:1 acetonitrile/water(2 mL), filtered, and purified by preparative LCMS to give theintermediate5-[3-[4-({4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzyl}amino)-1,2,5-oxadiazol-3-yl]-5-oxo-1,2,4-oxadiazol-4(5H)-yl]-2-fluorobenzonitriletrifluoroacetate. This material was diluted with ethanol (1 mL), treatedwith 2.0 M sodium hydroxide in water (0.1 mL), and stirred for 45 min.The reaction mixture was quenched with acetic acid (50 μL, 0.9 mmol),filtered, and purified by preparative LCMS to give the desired product(1 mg, 11%). LCMS for C₂₂H₂₃FN₇O₄S (M+H)⁺: m/z=500.0.

Example 62N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-[(pyridin-3-ylmethyl)amino]-1,2,5-oxadiazole-3-carboximidamidetrifluoroacetate

Step 1.4-(3-Bromo-4-fluorophenyl)-3-{4-[(pyridin-3-ylmethyl)amino]-1,2,5-oxadiazol-3-yl}-1,2,4-oxadiazol-5(4H)-onetrifluoroacetate

A solution ofN-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-2,2,2-trifluoroacetamide(50 mg, 0.11 mmol), nicotinyl alcohol (14 μL, 0.15 mmol), andtriphenylphosphine (42 mg, 0.16 mmol) in tetrahydrofuran (0.35 mL) at 0°C. was treated with diisopropyl azodicarboxylate (34 μL, 0.17 mmol). Thereaction mixture was stirred at 25° C. for 16 h and purified bypreparative LCMS to give the desired product (4 mg, 6%). LCMS forC₆H₁₁BrFN₆O₃ (M+H)⁺: m/z=432.9, 434.9.

Step 2.N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-[(pyridin-3-ylmethyl)amino]-1,2,5-oxadiazole-3-carboximidamidetrifluoroacetate

This compound was prepared according to the procedure of Example 38,Step 2, using4-(3-bromo-4-fluorophenyl)-3-{4-[(pyridin-3-ylmethyl)amino]-1,2,5-oxadiazol-3-yl}-1,2,4-oxadiazol-5(4H)-onetrifluoroacetate as the starting material. LCMS for C₁₅H₁₃BrFN₆O₂(M+H)⁺: m/z=406.9, 408.9.

Example 63N-(3-Cyano-4-fluorophenyl)-N′-hydroxy-4-[(pyridin-4-ylmethyl)amino]-1,2,5-oxadiazole-3-carboximidamidetrifluoroacetate

A solution ofN-{4-[4-(3-cyano-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}isonicotinamidetrifluoroacetate (37 mg, 72 μmol) in pyridine (1.5 mL) at 0° C. wastreated with phosphorus pentachloride (45 mg, 0.22 mmol) and stirred for3 h. The reaction mixture was concentrated, diluted with ethanol (2.5mL), treated with sodium cyanoborohydride (14 mg, 0.22 mmol), andstirred for 16 h. The reaction mixture was purified by preparative LCMSto give the intermediate2-fluoro-5-[5-oxo-3-{4-[(pyridin-4-ylmethyl)amino]-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-4(5H)-yl}benzonitriletrifluoroacetate. This material was diluted with ethanol (1 mL), treatedwith 2.0 M sodium hydroxide in water (0.2 mL), and stirred for 45 min.Purification of the crude reaction mixture by preparative HPLC gave thedesired product (8 mg, 24%). LCMS for C₁₆H₁₃FN₇O₂ (M+H)⁺: m/z=354.0.

Example 644-[(3-Cyanobenzyl)amino]-N-(3-cyano-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide

A solution of3-cyano-N-{4-[4-(3-cyano-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}benzamide(30 mg, 72 μmol) in benzene (2 mL) at 0° C. was treated with phosphoruspentachloride (45 mg, 0.22 mmol) and stirred at 90° C. for 2 h. Thereaction mixture was concentrated, diluted with ethanol (2.5 mL),treated with sodium cyanoborohydride (14 mg, 0.22 mmol), and stirred for16 h. The reaction mixture was purified by preparative LCMS to give theintermediate5-[3-{4-[(3-cyanobenzyl)amino]-1,2,5-oxadiazol-3-yl}-5-oxo-1,2,4-oxadiazol-4(5H)-yl]-2-fluorobenzonitrile.This material was diluted with ethanol (1 mL), treated with 2.0 M sodiumhydroxide in water (0.2 mL), and stirred for 45 min. Purification of thecrude reaction mixture by preparative HPLC gave the desired product (3mg, 11%). LCMS for C₁₈H₁₃FN₇O₂ (M+H)⁺: m/z=378.0.

Example 65N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-[(1H-tetrazol-5-ylmethyl)amino]-1,2,5-oxadiazole-3-carboximidamide

Step 1.N-{4-[4-(3-Bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-1H-tetrazole-5-carboxamide

A solution of3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one(50 mg, 0.15 mmol) and 4-dimethylaminopyridine (11 mg, 88 μmol) inacetonitrile (0.8 mL) and pyridine (0.12 mL) was treated with phosphorylchloride (42 μL, 0.45 mmol) and stirred for 1 h. The reaction mixturewas concentrated, dissolved in 3:1 acetonitrile/water, and purified bypreparative LCMS to give the desired product (14 mg, 22%). LCMS forC₁₂H₆BrFN₉O₄ (M+H)⁺: m/z=437.8, 439.9.

Step 2.N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-[(1H-tetrazol-5-ylmethyl)amino]-1,2,5-oxadiazole-3-carboximidamide

A solution ofN-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-1H-tetrazole-5-carboxamide(12 mg, 27 μmol) in pyridine (0.3 mL) was treated with phosphoruspentachloride (13 mg, 60 μmol) at 25° C. The reaction mixture wasstirred at 0° C. for 2 h, concentrated, rediluted with toluene andconcentrated to a residue. This material was diluted with ethanol (1mL), treated with sodium cyanoborohydride (5 mg, 82 μmol), and stirredfor 2 h. The reaction mixture was concentrated, diluted with ethanol (1mL), treated with 2.0 M sodium hydroxide in water (0.2 mL), and stirredfor 45 min. Purification of the crude reaction mixture by preparativeLCMS gave the desired product (2 mg, 19%). LCMS for C₁₁H₁₀BrFN₉O₂(M+H)⁺: m/z=398.0, 400.0.

Example 66N-(Acetyloxy)-4-amino-N-(3-chloro-4-fluorophenyl)-1,2,5-oxadiazole-3-carboximidamide

A solution of4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide(0.1 g, 0.37 mmol) in acetic anhydride was stirred for 2 h. The reactionmixture was concentrated and purified by preparative LCMS to give thedesired product (625 mg, 54%). LCMS for C₁₁H₁₀ClFN₅O₃ (M+H)⁺: m/z=314.1.

Example 674-Amino-N-(3-chloro-4-fluorophenyl)-N′-(propionyloxy)-1,2,5-oxadiazole-3-carboximidamide

A solution of4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide(0.1 g, 0.37 mmol) and N,N-diisopropylethylamine (0.16 mL, 0.92 mmol) indichloromethane (4 mL) was treated with propanoyl chloride (38 μL, 0.44mmol) and stirred for 1 h. The reaction mixture was concentrated andpurified by preparative LCMS to give the desired product (57 mg, 47%).LCMS for C₁₂H₁₂ClFN₅O₃ (M+H)⁺: m/z=328.0.

Example 684-Amino-N′-{[(benzylamino)carbonyl]oxy}-N-(3-chloro-4-fluorophenyl)-1,2,5-oxadiazole-3-carboximidamide

A solution of4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide(50 mg, 0.18 mmol) and N,N-diisopropylethylamine (64 μL, 0.37 mmol) indichloromethane (2 mL) was treated with benzyl isocyanate (29 mg, 0.22mmol) and stirred for 3 h. The reaction mixture was concentrated andpurified by preparative LCMS to give the desired product (18 mg, 24%).LCMS for C₁₇H₁₅ClFN₆O₃ (M+H)⁺: m/z=405.0.

Example 69N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-morpholin-4-yl-1,2,5-oxadiazole-3-carboximidamide

Step 1.4-[(E,Z)-(Hydroxyimino)(morpholin-4-yl)methyl]-1,2,5-oxadiazol-3-amine

This compound was prepared according to the procedure of Example 1 usingmorpholine as the starting material. LCMS for C₇H₁₂N₅O₃ (M+H)⁺:m/z=214.0.

Step 2. N′-Hydroxy-4-morpholin-4-yl-1,2,5-oxadiazole-3-carboximidamide

A solution of4-[(E,Z)-(hydroxyimino)(morpholin-4-yl)methyl]-1,2,5-oxadiazol-3-amine(0.1 g, 0.47 mmol) in 1,2-ethanediol (1.6 mL) was treated with potassiumhydroxide (94 mg, 1.7 mmol) and stirred at 130° C. for 7 h. The reactionmixture was treated with additional potassium hydroxide (53 mg, 0.94mmol) and stirred at 140° C. for 5.5 h. The reaction mixture was cooledto 0° C., neutralized with 6.0 M HCl, and purified by preparative LCMSto give the desired product desired product (70 mg, 70%). LCMS forC₇H₁₂N₅O₃ (M+H)⁺: m/z=214.1.

Step 3. N-Hydroxy-4-morpholin-4-yl-1,2,5-oxadiazole-3-carboximidoylchloride

A solution ofN′-hydroxy-4-morpholin-4-yl-1,2,5-oxadiazole-3-carboximidamide (66 mg,0.3 mmol) in 6.0 M HCl (0.62 mL) at 5-10° C. was treated with a solutionof sodium nitrite (32 mg, 0.47 mmol) in water (0.5 mL) dropwise andstirred for 2 h at 0° C. The suspension was filtered and the solidwashed with ice water to give desired product (22 mg, 30%). The filtratewas extracted with ethyl acetate (30 mL) which was washed with brine (10mL), filtered and concentrated to give additional product (23 mg, 32%)that contained minor impurities. The combined material was usedimmediately in the next step.

Step 4.N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-morpholin-4-yl-1,2,5-oxadiazole-3-carboximidamide

A solution ofN-Hydroxy-4-morpholin-4-yl-1,2,5-oxadiazole-3-carboximidoyl chloride (40mg, 0.17 mmol) and 3-bromo-4-fluoroaniline (49 mg, 0.26 mmol) in ethanol(1 mL) was treated with a solution of N,N-diisopropylethylamine (45 μL,0.26 mmol) in acetonitrile (1 mL) and stirred for 62 h. The reactionmixture was purified by preparative HPLC to give the desired product (32mg, 48%). LCMS for C₁₃H₁₄ClFN₅O₃ (M+H)⁺: m/z=386.0, 388.0.

Example 704-Amino-N′-hydroxy-N-[3-(3-hydroxyprop-1-yn-1-yl)phenyl]-1,2,5-oxadiazole-3-carboximidamide

A solution of4-amino-N′-hydroxy-N-(3-iodophenyl)-1,2,5-oxadiazole-3-carboximidamide(19 mg, 55 μmol), 2-propyn-1-ol (3.6 μL, 62 μmol),bis(triphenylphosphine)palladium(II) chloride (1 mg, 2 μmol), and copper(I) iodide (0.4 mg, 2 μmol) in N,N-dimethylformamide (0.5 mL) wastreated with N,N-diethylamine (74 μl, 0.72 mmol) and heated in themicrowave at 120° C. for 15 min. The reaction mixture was diluted with1:1 acetonitrile/water (1.5 mL), filtered, and purified by preparativeLCMS to give the desired product (4 mg, 28%). LCMS for C₁₂H₁₂N₅O₃(M+H)⁺: m/z=274.0.

Further example compounds of the invention are provided below in Table1.

TABLE 1 Ex. Prep. MS No. Structure Name Method (M + 1) 71

N-{4-[(E,Z)-[(3- Chlorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}cyclopentanecarboxamide Ex. 35 350.072

N-{4-[(E,Z)-[(3- Chlorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}nicotinamide trifluoroacetate Ex. 35359.0 73

N-{4-[(E,Z)-[(3- Chlorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}isonicotinamide trifluoroacetate Ex.35 359.0 74

N-{4-[(E,Z)-[(3- Chlorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-methoxybenzamide Ex. 35 388.1 75

N-{4-[(E,Z)-[(3- Chlorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-methoxybenzamide Ex. 35 387.9 76

N-{4-[(E,Z)-[(3- Chlorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-4-methoxybenzamide Ex. 35 388.0 77

2-Chloro-N-{4-[(E,Z)-[(3- chlorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}benzamide Ex. 35 391.9 78

3-Chloro-N-{4-[(E,Z)-[(3- chlorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}benzamide Ex. 35 391.9 79

4-Chloro-N-{4-[(E,Z)-[(3- chlorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}benzamide Ex. 35 391.9 80

N-{4-[(E,Z)-[(3- Chlorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3,3-dimethylbutanamide Ex. 35 352.081

4-Amino-N-(3-bromophenyl)-N′- hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 1 298.0, 300.0 82

4-Amino-N-(3-bromo-4- methylphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 1 312.1, 314.1 83

4-Amino-N-(3-chloro-4- methoxyphenyl)-N′-hydroxy- 1,2,5-oxadiazole-3-carboximidamide Ex. 1 284.1 84

4-Amino-N-(3,5- dimethylphenyl)-N′-hydroxy- 1,2,5-oxadiazole-3-carboximidamide Ex. 1 248.2 85

4-Amino-N′-hydroxy-N-(2- methylbenzyl)-1,2,5-oxadiazole-3-carboximidamide Ex. 1 248.2 86

4-Amino-N′-hydroxy-N-(3- methylbenzyl)-1,2,5-oxadiazole-3-carboximidamide Ex. 1 248.2 87

4-Amino-N′-hydroxy-N-(4- methylbenzyl)-1,2,5-oxadiazole-3-carboximidamide Ex. 1 248.2 88

4-Amino-N′-hydroxy-N-[2- (trifluoromethypbenzyl]-1,2,5-oxadiazole-3-carboximidamide Ex. 1 302.1 89

4-Amino-N′-hydroxy-N-[4- (trifluoromethyl)benzyl]-1,2,5-oxadiazole-3-carboximidamide Ex. 1 302.1 90

4-Amino-N-(3-ethylphenyl)-N′- hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 1 248.1 91

4-Amino-N-(3,4- dichlorophenyl)-N′-hydroxy- 1,2,5-oxadiazole-3-carboximidamide Ex. 1 288.1 92

4-Amino-N-(3,5- dichlorophenyl)-N′-hydroxy- 1,2,5-oxadiazole-3-carboximidamide Ex. 1 288.1 93

4-Amino-N-biphenyl-3-yl-N′- hydroxy-1,2,5-oxadiazole-3- carboximidamideEx. 1 296.1 94

4-Amino-N-(2-fluorophenyl)-N′- hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 1 238.1 95

4-Amino-N-(3-chloro-4- methylbenzyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 1 282.1 96

4-Amino-N-(4-fluorophenyl)-N′- hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 1 238.1 97

4-Amino-N-(2,3- dimethylphenyl)-N′-hydroxy- 1,2,5-oxadiazole-3-carboximidamide Ex. 1 248.2 98

N-{4-[(E,Z)-[(3- Chlorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-4-iodobenzamide Ex. 35 483.8 99

4-Amino-N-(4-chloro-3- methylphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 1 268.2 100

4-Amino-N′-hydroxy-N-[3- (methylthio)phenyl]-1,2,5-oxadiazole-3-carboximidamide Ex. 1 266.0 101

4-Amino-N-(3-chloro-2- methylphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 1 268.1 102

4-Amino-N-(3-fluoro-2- methylphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 1 252.1 103

4-Amino-N′-hydroxy-N-(3- vinylphenyl)-1,2,5-oxadiazole-3-carboximidamide Ex. 1 246.1 104

4-Amino-N-(3-ethynylphenyl)- N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 1 244.0 105

4-Amino-N-(4-fluoro-3- methylphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 1 252.0 106

4-Amino-N′-hydroxy-N-(3- iodophenyl)-1,2,5-oxadiazole-3- carboximidamideEx. 1 345.9 107

4-Amino-N′-hydroxy-N-(3- isopropylphenyl)-1,2,5-oxadiazole-3-carboximidamide Ex. 1 262.2 108

4-Amino-N-(3-bromo-4- fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 1 316.1 109

4-Amino-N′-hydroxy-N-(4- phenylbutyl)-1,2,5-oxadiazole-3-carboximidamide Ex. 1 276.2 110

4-Amino-N′-hydroxy-N-[3-(1,3- oxazol-5-yl)phenyl]-1,2,5-oxadiazole-3-carboximidamide Ex. 1 287.0 111

N-{4-[(E,Z)-[(3- Chlorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-4-cyanobenzamide Ex. 35 382.9 112

4-Amino-N′-hydroxy-N-[1- phenylethyl]-1,2,5-oxadiazole-3-carboximidamide Ex. 1 248.2 113

4-Amino-N′-hydroxy-N-1- naphthyl-1,2,5-oxadiazole-3- carboximidamide Ex.1 270.2 114

4-Amino-N′-hydroxy-N-2- naphthyl-1,2,5-oxadiazole-3- carboximidamide Ex.1 270.2 115

4-Amino-N-(3-chloro-2- fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 1 272.1 116

N-{4-[(E,Z)-{[4-Fluoro-3- (trifluoromethyl)phenyl]amino}(hydroxyimino)methyl]-1,2,5- oxadiazol-3-yl}nicotinamidetrifluoroacetate Ex. 35 411.1 117

N-{4-[(E,Z)-{[4Fluoro-3- (trifluoromethyl)phenyl]amino}(hydroxyimino)methyl]-1,2,5- oxadiazol-3-yl}isonicotinamidetrifluoroacetate Ex. 35 411.1 118

4-Amino-N-(3- cyclopropylphenyl)-N′-hydroxy- 1,2,5-oxadiazole-3-carboximidamide Ex. 1 260.2 119

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}benzamide Ex. 35 420.0, 421.9 120

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}nicotinamide trifluoroacetate Ex. 35420.9, 422.9 121

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}isonicotinamide trifluoroacetate Ex.35 421.0, 422.9 122

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-4-cyanobenzamide Ex. 35 444.9,446.9 123

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-cyanobenzamide Ex. 35 445.0,447.0 124

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-naphthamide Ex. 35 470.0, 472.0125

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-1-naphthamide Ex. 35 470.0, 472.0126

1-Acetyl-N-{4-[(E,Z)-[(3-bromo- 4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}piperidine-4-carboxamide Ex. 35469.0, 471.0 127

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-furamide Ex. 35 409.9, 411.9 128

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}thiophene-2-carboxamide Ex. 35425.9, 427.9 129

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide Ex. 35 553.9, 556.0 130

4-(Acetylamino)-N-{4-[(E,Z)- [(3-bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}benzamide Ex. 35 476.9, 479.0 131

tert-Butyl {4-[({4-[(E,Z)-[(3- bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}amino)carbonyl]benzyl}carba- mateEx. 41 548.9, 551.0 132

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-1-benzothiophene-2- carboxamide Ex.41 475.9, 477.9 133

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-1,3-thiazole-4-carboxamide Ex. 41426.9, 428.9 134

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-1-benzothiophene-3- carboxamide Ex.41 475.9, 477.9 135

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}thiophene-3-carboxamide Ex. 41425.8, 427.9 136

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-1H-imidazole-2-carboxamide Ex. 41409.9, 411.9 137

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-4-methyl-1,2,3-thiadiazole-5-carboxamide Ex. 41 441.9, 443.9 138

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-1,2,3-thiadiazole-4- carboxamideEx. 41 427.9, 429.9 139

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2,1-benzisoxazole-3- carboxamideEx. 41 460.9, 462.9 140

4-(Aminomethyl)-N-{4-[(E,Z)- [(3-bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}benzamide trifluoroacetate Ex. 41448.9, 450.9 141

N-(3-Bromo-4-fluorophenyl)-N′- hydroxy-4-({[(2-phenylethyl)amino]carbonyl} amino)-1,2,5-oxadiazole-3- carboximidamideEx. 43 463.0, 465.0 142

N-(3-Bromo-4-fluorophenyl)-4- {[(cyclopentylamino)carbonyl]amino}-N′-hydroxy-1,2,5- oxadiazole-3-carboximidamide Ex. 43 426.9,428.9 143

N-(3-Bromo-4-fluorophenyl)-4- ({[(3- cyanophenyl)amino]carbonyl}amino)-N′-hydroxy-1,2,5- oxadiazole-3-carboximidamide Ex. 43 459.9,461.9 144

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-tert-butyl-1-methyl-1H-pyrazole-5-carboxamide Ex. 35 480.0, 482.0 145

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-methoxyacetamide Ex. 35 387.9,389.9 146

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}cyclopentanecarboxamide Ex. 35412.0, 413.9 147

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}butanamide Ex. 35 385.9, 388.0 148

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-methylpropanamide Ex. 35 386.0,387.9 149

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}propanamide Ex. 35 371.9, 373.9 150

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}cyclohexanecarboxamide Ex. 35 426.0,427.9 151

4-Amino-N-(2,3- dichlorophenyl)-N′-hydroxy- 1,2,5-oxadiazole-3-carboximidamide Ex. 47 288.0 152

4-Amino-N-(3-chlorophenyl)-N′- hydroxy-N-methyl-1,2,5-oxadiazole-3-carboximidamide Ex. 1 268.1 153

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-1H-benzimidazole-5- carboxamidetrifluoroacetate Ex. 35 460.0, 462.0 154

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-phenoxyacetamide Ex. 35 449.9,451.8 155

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}cyclobutanecarboxamide Ex. 35 398.0,400.0 156

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-methylbutanamide Ex. 35 400.0,402.0 157

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-pyridin-3-ylpropanamidetrifluoroacetate Ex. 35 449.0, 450.9 158

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}quinoline-6-carboxamide Ex. 35470.9, 472.9 159

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(4- chlorophenoxy)acetamide Ex.35 483.9, 485.9 160

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(4- bromophenoxy)acetamide Ex. 35527.8, 529.9, 531.8 161

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(4- fluorophenoxy)acetamide Ex.35 468.0, 470.0 162

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(4-tert- butylphenoxy)acetamideEx. 35 506.0, 508.0 163

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(3- chlorophenoxy)acetamide Ex.35 483.9, 485.9 164

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(3,4- dichlorophenoxy)acetamideEx. 35 518.0, 519.9, 522.0 165

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(2-naphthyloxy)acetamide Ex. 35500.1, 502.0 166

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(2,3- dichlorophenoxy)acetamideEx. 35 517.8, 519.8, 521.8 167

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(4-chlorophenoxy)-2-methylpropanamide Ex. 35 511.9, 513.9 168

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(2- chlorophenoxy)acetamide Ex.35 483.8, 485.9 169

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(3- methoxyphenoxy)acetamide Ex.35 480.0, 481.9 170

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(4- methoxyphenoxy)acetamide Ex.35 479.9, 481.9 171

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(2- methoxyphenoxy)acetamide Ex.35 480.0, 482.0 172

Benzyl {4-[(E,Z)-[(3-bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}carbamate Ex. 35 449.9, 451.9 173

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}acetamide Ex. 35 357.9, 359.9 174

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}piperidine-1-carboxamide Ex. 48427.0, 429.0 175

N-(3-Bromo-4-fluorophenyl)-4- ({[(3- cyanophenyl)(methyl)amino]car-bonyl}amino)-N′-hydroxy-1,2,5- oxadiazole-3-carboximidamide Ex. 48473.9, 476.0 176

4-Amino-N′-hydroxy-N-(6- methylpyridin-2-yl)-1,2,5-oxadiazole-3-carboximidamide trifluoroacetate Ex. 45 235.1 177

4- ({[Benzyl(methyl)amino]carbon- yl}amino)-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5- oxadiazole-3-carboximidamide Ex. 48463.0, 464.9 178

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-phenylacetamide Ex. 35 434.0,436.0 179

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(3- methoxyphenyl)acetamide Ex.35 464.0, 466.0 180

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(4- methoxyphenyl)acetamide Ex.35 464.0, 466.0 181

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(2- methoxyphenyl)acetamide Ex.35 464.0, 466.0 182

4-Amino-N-(2,4- dichlorophenyl)-N′-hydroxy- 1,2,5-oxadiazole-3-carboximidamide Ex. 45 288.0 183

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-cyanobenzamide Ex. 35 444.9,446.9 184

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-(3- bromophenyl)propanamide Ex.35 525.9, 527.8, 529.8 185

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-(4- bromophenyl)propanamide Ex.35 525.8, 527.8, 529.8 186

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-(4- chlorophenyl)propanamide Ex.35 481.9, 483.9 187

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-(3- chlorophenyl)propanamide Ex.35 481.9, 483.9 188

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-(2- fluorophenyl)propanamide Ex.35 466.0, 467.9 189

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-(3- fluorophenyl)propanamide Ex.35 465.9, 467.9 190

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-(2- chlorophenyl)propanamide Ex.35 481.9, 483.9 191

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-(3- methylphenyl)propanamide Ex.35 462.0, 464.0 192

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-(3-(trifluoromethyl)phenyl)propan- amide Ex. 35 515.9, 517.9 193

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-(4- fluorophenyl)propanamide Ex.35 465.9, 468.0 194

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-(2- methoxyphenyl)propanamide Ex.35 477.9, 479.9 195

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-(3- methoxyphenyl)propanamide Ex.35 477.9, 480.0 196

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-(4- methoxyphenyl)propanamide Ex.35 477.9, 479.9 197

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-(4- methylphenyl)propanamide Ex.35 462.0, 463.9 198

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-[4-(trifluoromethyl)phenyl]propan- amide Ex. 35 515.9, 517.9 199

3-[2,5- Bis(trifluoromethyl)phenyl]-N- {4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxy- imino)methyl]-1,2,5-oxadiazol-3-yl}propanamide Ex. 35 583.9, 585.9 200

3-[3,5- Bis(trifluoromethyl)phenyl]-N- {4-[(EZ)-[(3-bromo-4-fluoropheny)amino](hydroxy- imino)methyl]-1,2,5-oxadiazol-3-yl}propanamide Ex. 35 583.9, 585.9 201

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-methyl-3- phenylpropanamide Ex.35 462.0, 464.0 202

2-Benzyl-N-{4-[(E,Z)-[(3- bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3,3-dimethylbutanamide Ex. 35504.0, 506.0 203

4-Amino-N-(5-chloro-2- methoxyphenyl)-N′-hydroxy- 1,2,5-oxadiazole-3-carboximidamide Ex. 1 284.1 204

4-Amino-N-(5-chloro-2- methylphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 1 268.1 205

4-Amino-N-(5-chloro-2- nitrophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 47 299.0 206

4-Amino-N-(5-chloro-2- fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 47 272.1 207

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-1-[4- (trifluoromethyl)pyrimidin-2-yl]piperidine-4-carboxamide Ex. 35 573.0, 575.0 208

1-Benzyl-N-{4-[(E,Z)-[(3- bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-tert-butyl-1H-pyrazole-5-carboxamide Ex. 35 556.0, 558.0 209

2-(Benzyloxy)-N-{4-[(E,Z)-[(3- bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}acetamide Ex. 35 463.9, 466.0 210

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-1-(4-chlorophenyl)cyclopentanecarbox- amide Ex. 35 521.9, 523.9 211

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-phenoxybenzamide Ex. 35 511.9,513.9 212

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2,4,6-trichlorobenzamide Ex. 35521.8, 523.8, 525.8 213

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-methoxybenzamide Ex. 35 449.9,451.9 214

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-methoxybenzamide Ex. 35 449.9,451.9 215

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2,2-diphenylacetamide Ex. 35 510.0,512.0 216

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-4- (trifluoromethoxy)benzamide Ex.35 503.9, 505.9 217

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-4-methoxybenzamide Ex. 35 449.9,451.8 218

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3,4-dimethoxybenzamide Ex. 35479.9, 481.9 219

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(2-nitrophenoxy)acetamide Ex. 35494.9, 496.9 220

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-chloronicotinamidetrifluoroacetate Ex. 35 454.9, 456.9 221

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}biphenyl-4-carboxamide Ex. 35 496.0,497.9 222

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(2,6-dichlorobenzyl)-1,3-thiazole-4-carboxamide Ex. 35 584.8, 586.8, 588.8 223

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2,6-dimethoxybenzamide Ex. 35479.9, 482.0 224

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3 yl}-4-nitrobenzamide Ex. 35 464.9, 466.9225

5-Bromo-N-{4-[(E,Z)-[(3- bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}nicotinamide trifluoroacetate Ex. 35498.8, 500.8, 502.8 226

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3,3-dimethylbutanamide Ex. 35413.9, 415.9 227

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(2-thienyl)acetamide Ex. 35439.9, 441.9 228

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-4-phenylbutanamide Ex. 35 462.0,464.0 229

4-Amino-N-(2-bromo-5- chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 47 332.0, 334.0 230

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2,2-dimethylpropanamide Ex. 35400.0, 401.9 231

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-4-(morpholin-4- ylmethyl)benzamidetrifluoroacetate Ex. 35 519.0, 521.0 232

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-4-[(1,1- dioxidothiomorpholin-4-yl)methyl]benzamide trifluoroacetate Ex. 35 567.0, 569.0 233

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-1-(phenylacetyl)piperidine-4-carboxamide Ex. 53 545.0, 547.6 234

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-1- (methylsulfonyl)piperidine-4-carboxamide Ex. 53 505.0, 507.0 235

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-pyridin-4-yl-1,3-thiazole-4-carboxamide trifluoroacetate Ex. 35 504.0, 506.0 236

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-nitrobenzamide Ex. 35 464.9,466.9 237

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-nitrobenzamide Ex. 35 464.9,466.9 238

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-1-isopropylpiperidine-4-carboxamide trifluoroacetate Ex. 55 469.0, 471.0 239

tert-Butyl 4-{4-[({4-[(E,Z)-[(3- bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}amino)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate Ex. 51 510.0, 512.0* 240

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-phenyl-1,3-thiazole-4-carboxamide Ex. 35 502.9, 504.9 241

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-methyl-1,3-thiazole-4-carboxamide Ex. 35 441.0, 443.0 242

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-piperidin-4-yl-1,3-thiazole-4-carboxamide hydrochloride Ex. 52 510.0, 512.0 243

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(4- cyanophenoxy)acetamide Ex. 57475.0, 476.9 244

tert-Butyl 3-[({4-[(E,Z)-[(3- bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}amino)carbonyl]piperidine-1-carboxylate Ex. 51 527.0, 529.0 245

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-3-(3- nitrophenyl)propanamide Ex.51 493.0, 494.9 246

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(3-nitrophenoxy)acetamide Ex. 51494.9, 497.0 247

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(4-nitrophenoxy)acetamide Ex. 51494.9, 496.9 248

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}piperidine-3-carboxamidetrifluoroacetate Ex. 52 426.9, 429.0 249

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-4-methyl-2-pyridin-3-yl-1,3-thiazole-5-carboxamide trifluoroacetate Ex. 57 518.0, 520.0 250

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-4-methyl-1,3-thiazole-5-carboxamide Ex. 57 441.0, 443.0 251

2-Amino-N-{4-[(E,Z)-[(3- bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-1,3-thiazole-4-carboxamidetrifluoroacetate Ex. 57 442.0, 444.0 252

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-4-methyl-2-pyrazin-2-yl-1,3-thiazole-5-carboxamide trifluoroacetate Ex. 51 519.0, 521.0 253

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3- thiazole-5-carboxamide Ex. 51 585.0, 587.0254

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2,4-dimethyl-1,3-thiazole-5-carboxamide Ex. 57 455.0, 457.0 255

1-Acetyl-N-{4-[(E,Z)-[(3-bromo- 4-fluorophenyl)amino]-(hydroxyimino)methyl]-1,2,5- oxadiazol-3-yl}pyrrolidine-2- carboxamideEx. 51 454.9, 456.9 256

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-1,5-dimethyl-1H-pyrazole-3-carboxamide Ex. 35 437.9, 439.9 257

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-5-chloro-1-methyl-1H-pyrazole-4-carboxamide Ex. 35 457.9, 459.9 258

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-1,3-dimethyl-1H-pyrazole-5-carboxamide Ex. 35 438.0, 440.0 259

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-1-methyl-1H-imidazole-2-carboxamide Ex. 51 424.1, 426.0 260

4-[(Acetylamino)methyl]-N-{4- [(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxy- imino)methyl]-1,2,5-oxadiazol-3-yl}benzamide Ex. 56 491.0, 493.0 261

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-4-methylpiperidine-4- carboxamidetrifluoroacetate Ex. 58 441.0, 443.0 262

1-Acetyl-N-{4-[(E,Z)-[(3-bromo- 4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}piperidine-3-carboxamide Ex. 53469.0, 471.0 263

1-Acetyl-N-{4-[(E,Z)-[(3-bromo- 4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-4-methylpiperidine-4- carboxamideEx. 53 483.0, 485.0 264

1-Acetyl-N-{4-[(E,Z)-[(3-bromo- 4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-4-phenylpiperidine-4- carboxamideEx. 53 545.0, 547.0 265

4-(Benzylamino)-N-(3-bromo-4- fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 49 406.1, 408.0 266

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-1-ethylpiperidine-3- carboxamidetrifluoroacetate Ex. 55 455.0, 457.0 267

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-4-ethylpiperazine-1- carboxamidetrifluoroacetate Ex. 48 456.0, 458.0 268

4-Acetyl-N-{4-[(E,Z)-[(3-bromo- 4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}piperazine-1-carboxamide Ex. 48470.0, 472.0 269

N-{4-[(E,Z)-[(3-Bromo-4- fluorophenyl)amino](hydroxy-imino)methyl]-1,2,5-oxadiazol-3- yl}-2-(1-ethylpiperidin-4-yl)-1,3-thiazole-4-carboxamide trifluoroacetate Ex. 55 538.0, 540.0 270

4-Amino-N-(3-cyano-4- fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 1 263.1 271

N-(3-Bromo-4-fluorophenyl)-N′- hydroxy-4-[(1,3-thiazol-4-ylmethyl)amino]-1,2,5- oxadiazole-3-carboximidamide Ex. 60 413.0, 415.0272

N-(3-Bromo-4-fluorophenyl)-4- [(4-cyanobenzyl)amino]-N′-hydroxy-1,2,5-oxadiazole-3- carboximidamide Ex. 60 431.0, 433.0 273

4-Amino-N-(3-chloro-5- fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 1 272.0 274

4-Amino-N-[3- (difluoromethyl)phenyl]-N′- hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 1 270.1 275

N-(3-Bromo-4-fluorophenyl)-N′- hydroxy-4-{[(1-methylpiperidin-4-y)methyl]amino}-1,2,5- oxadiazole-3-carboximidamide trifluoroacetateEx. 60 427.0, 429.0 276

N-(3-Bromo-4-fluorophenyl)-N′- hydroxy-4-{[4-(piperazin-1-ylmethypbenzyl]amino}-1,2,5- oxadiazole-3-carboximidamidebis(trifluoroacetate) Ex. 60 504.0, 506.0 277

N-(3-Bromo-4-fluorophenyl)-4- ({4-[(4-ethylpiperazin-1-yl)methyl]benzyl}amino)-N′- hydroxy-1,2,5-oxadiazole-3- carboximidamidebis(trifluoroacetate) Ex. 60 532.2, 534.2 278

4-Amino-N′-hydroxy-N-(3- hydroxyphenyl)-1,2,5-oxadiazole-3-carboximidamide Ex. 1 236.1 279

4-Amino-N-(3-chloro-4- fluorophenyl)-N′- (isobutyryloxy)-1,2,5-oxadiazole-3-carboximidamide Ex. 67 342.0 280

4-Amino-N-(3-chloro-4- fluorophenyl)-N′-[(3- methylbutanoyl)oxy]-1,2,5-oxadiazole-3-carboximidamide Ex. 67 356.0 281

4-Amino-N′-(benzoyloxy)-N-(3- chloro-4-fluorophenyl)-1,2,5-oxadiazole-3-carboximidamide Ex. 67 376.0 282

4-Amino-N-(3-chloro-4- fluorophenyl)-N′-[(2,2-dimethylpropanoyl)oxy]-1,2,5- oxadiazole-3-carboximidamide Ex. 67 356.0283

4-Amino-N-[3- (cyanomethyl)phenyl]-N′- hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 1 259.1 284

4-Amino-N-(3-cyano-2- fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 1 263.1 285

4-Amino-N′-hydroxy-N-[3- (methoxymethyl)phenyl]-1,2,5-oxadiazole-3-carboximidamide Ex. 1 264.1 286

4-Amino-N′-hydroxy-N-[3-(3- methoxyprop-1-yn-1-yl)phenyl]-1,2,5-oxadiazole-3- carboximidamide Ex. 70 287.9 287

4-Amino-N′-hydroxy-N-(2- methyl-1,3-benzoxazol-4-yl)-1,2,5-oxadiazole-3- carboximidamide Ex. 1 275.0 288

4-Anilino-N-(3-bromo-4- fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide Ex. 69 392.0, 394.0 289

N-(3-Bromo-4-fluorophenyl)-N′- hydroxy-4-[(pyridin-4-ylmethyl)amino]-1,2,5- oxadiazole-3-carboximidamide trifluoroacetate Ex.63 406.9, 408.9 290

N-(3-Bromo-4-fluorophenyl)-4- [(3-cyanobenzyl)amino]-N′-hydroxy-1,2,5-oxadiazole-3- carboximidamide Ex. 64 430.9, 432.9 *([M −Boc + H] + H)⁺

Example A Human idoleamine 2,3-dioxygenasae (IDO) Enzyme Assay

Human idoleamine 2,3-dioxygenasae (IDO) with an N-terminal His tag wasexpressed in E. coli and purified to homogeneity. IDO catalyzes theoxidative cleavage of the pyrrole ring of the indole nucleus oftryptophan to yield IV′-formylkynurenine. The assays were performed atroom temperature as described in the literature using 95 nM IDO and 2 mMD-Trp in the presence of 20 mM ascorbate, 5 μM methylene blue and 0.2mg/mL catalase in 50 mM potassium phosphate buffer (pH 6.5). The initialreaction rates are recorded by continuously following the absorbanceincrease at 321 nm due to the formation of N′-formlylkynurenine. See:Sono, M., Taniguchi, T., Watanabe, Y., and Hayaishi, O. (1980) J. Biol.Chem. 255, 1339-1345 Compounds of the invention having an IC₅₀ less thanabout 100 μM were considered active.

Example B Determination of Inhibitor Activity in HeLa Cell-BasedIndoleamine 2,3-dioxygenase (IDO)/Kynurenine Assay

HeLa cells (#CCL-2) were obtained from the American Type Tissue CultureCollection (ATCC, Manassas, Va.) and routinely maintained in minimumessential medium (eagle) with 2 mM L-glutamine and Earle's BSS adjustedto contain 1.5 g/L sodium bicarbonate, 0.1 mM non-essential amino acids,1 mM sodium pyruvate and 10% fetal bovine serum (all from Invitrogen).Cells were kept at 37° C. in a humidified incubator supplied with 5%CO₂. The assay was performed as follows: HeLa cells were seeded in a 96well culture plate at a density of 5×10³ per well and grown overnight.On the next day, IFN-γ (50 ng/mL final concentration) and serialdilutions of compounds (in total volume of 200 μL culture medium) wereadded into cells. After 48 hours of incubation, 140 μL of thesupernatant per well was transferred to a new 96 well plate. 10 μL of6.1 N trichloroacetic acid (#T0699, Sigma) was mixed into each well andincubated at 50° C. for 30 min to hydrolyze N-formylkynurenine producedby indoleamine 2,3-dioxygenase to kynurenine. The reaction mixture wasthen centrifuged for 10 min at 2500 rpm to remove sediments. 100 μL ofthe supernatant per well was transferred to another 96 well plate andmixed with 100 μl of 2% (w/v) p-dimethylaminobenzaldehyde (#15647-7,Sigma-Aldrich) in acetic acid. The yellow color derived from Kynureninewas measured at 480 nm using a SPECTRAmax 250 microplate reader(Molecular Devices). L-kynurenine (#K8625, Sigma) was used as standard.The standards (240, 120, 60, 30, 15, 7.5, 3.75, 1.87 μM) were preparedin 100 μL culture media and mixed with equal volume of 2% (w/v)p-dimethylaminobenzaldehyde. The percent inhibition at individualconcentrations was determined and the average values of duplicates wereobtained. The data is analyzed by using nonlinear regression to generateIC₅₀ values (Prism Graphpad). See: Takikawa O, et al. (1988). Mechanismof interferon-gamma action. Characterization of indoleamine2,3-dioxygenase in cultured human cells induced by interferon-gamma andevaluation of the enzyme-mediated tryptophan degradation in itsanticellular activity. J. Biol. Chem. 263(4):2041-8. Compounds of theinvention having an IC₅₀ less than about 100 μM were considered active.

Example C Determination of Effect of IDO Inhibitors on T CellProliferation that is Suppressed by IDO-Expressing Dendritic Cells

Monocytes were collected from human peripheral mononuclear cells byleukophoresis. Monocytes were then seeded at a density of 1×10⁶cells/well in a 96 well plate, using RPMI 1640 medium supplemented with10% fetal bovine serum and 2 mM L-glutamine (all from Invitrogen).Adherent cells were retained on the plate after overnight culture at 37°C. Adherent monocytes were then stimulated for 5-7 days with 100 ng/mlGM-CSF (#300-03, PeproTech) and 250 ng/ml IL-4 (#200-04, PeproTech),followed by activation with 5 μg/mL LPS from Salmonella typhimurium(#437650, Sigma) and 50 ng/mL IFN-γ (#285-IF, R&D Systems) foradditional 2 days to induce dendritic cell maturation.

After dendritic cell activation, the medium was replaced with completedRPMI 1640 supplemented with 100-200 U/mL IL-2 (#CYT-209, ProSpec-TanyTechnoGene) and 100 ng/mL anti-CD3 antibody (#555336, PharMingen), Tcells (2-3×10⁵ cells/well), and serial dilutions of IDO compounds. Afterincubation for 2 more days, T cell proliferation was measured by BrdUincorporation assay, using a colorimetric Cell Proliferation ELISA kitper manufacturer's instruction (#1647229, Roche Molecular Biochemicals).Cells were continuously cultured for 16-18 hrs in presence of 10 μM BrdUlabeling solution. Then, the labeling medium was removed, and 200 μLFixDenat per well was added to the cells and incubated for 30 minutes atroom temperature. The FixDenat solution was removed and 100 μL/wellanti-BrdU-POD antibody conjugate working solution was added. Thereaction was carried out for 90 minutes at room temperature. Theantibody conjugate was then removed, and cells were rinsed three timeswith 200 μL/well washing solution. Finally, 100 μL/well of substratesolution was added and the results were obtained using a microplatereader (Spectra Max PLUS, Molecular Devices) during color development.Multiple readings at various time points were obtained to ensure thedata was within the linear range. The data was routinely obtained fromreplicated experiments, and appropriate controls were included. See:Terness P, et al. (2002). Inhibition of allogeneic T cell proliferationby indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation ofsuppression by tryptophan metabolites. J. Exp. Med. 196(4):447-57; andHwu P, et al. (2000). Indoleamine 2,3-dioxygenase production by humandendritic cells results in the inhibition of T cell proliferation. J.Immunol. 164(7):3596-9. Compounds of the invention having an IC₅₀ lessthan about 100 μM were considered active.

Example D In Vivo Testing of IDO Inhibitors for Antitumor Activity

In vivo anti-tumor efficacy can be tested using modified tumorallograft/xenograft protocols. For instance, it has been described inthe literature that IDO inhibition can syngerize with cytotoxicchemotherapy in immune-competent mice (Muller, A. J., et al). Thissynergy was shown to be dependent on T-cells by comparison of thesynergistic effects of an investigational IDO inhibitor in murine tumorxenograft models (e.g. B16 and related variants, CT-26, LLC) grown inimmune competent syngenic mice to that observed in syngenic mice treatedwith neutralizing anti-CD4 antibodies, or the same tumors grown inimmune-compromised mice (e.g. nu/nu).

The concept of differential anti-tumor effects in immune-competentversus immune-compromised mice may also permit testing ofinvestigational IDO inhibitors as single agents. For instance, LLCtumors grow well in their syngenic host strain, C57B1/6. However, ifthese mice are treated with the IDO inhibitor 1-MT (versus placebo) theformation of tumors is markedly delayed, implying that IDO inhibitionwas growth inhibitory (Friberg, M., et al). Following this logic, onecan examine the efficacy of IDO inhibition in the LLC xenograft tumormodel grown in C57Bl/6 immune competent mice and compare that to theeffects of IDO inhibitors on LLC tumor growth in nude or SCID mice (orC57Bl/6 mice treated with antibodies that neutralize T-cell activity).As the effects of relieving the tumor-mediated immune suppressiveactivity of IDO will likely differ depending on the immunogenicpotential of different tumor models, genetic modifications can be madeto the tumor cells to increase their immunogenic potential. Forinstance, expression of GM-CSF in B16.F10 cells increases theirimmunogenic potential (Dranoff, G., et al). As such, in some tumormodels (e.g. B16.F10) one can generate [poly]clones that express immunestimulatory proteins such as GM-CSF and test the growth inhibitoryeffects of IDO inhibitors against tumors established from these tumorcells in both immune-competent and compromised mice.

A third avenue for assessing the efficacy of IDO inhibitors in vivoemploys ‘pre-immunization’ murine tumor allograft/xenograft models. Inthese models, immune-competent mice are sensitized to a specific tumorantigen or antigens to mimic a therapeutic anti-tumor vaccination. Thisprimes the mice for an anti-tumor response mediated by the immune systemwhen mice are subsequently challenged with murine tumor cell lines(possessing similar tumor antigens to those used for immunization) inxenograft experiments. Expression of IDO has been shown to blunt theanti-tumor response and allow xenografts to grow more rapidly.Importantly, the growth of tumors in this model is inhibited by the IDOinhibitor 1-MT (Uyttenhove, C., et al). This model is particularlyattractive as IDO activity is permissive for P815 tumor growth andspecific inhibition of IDO should therefore growth inhibitory.

Lastly, therapeutic immunization may be used to evaluate the impact ofIDO inhibitors in vivo. For example, it has been demonstrated usingB16-BL6 cells that one can challenge Blk/6 mice with an intravenousinjection of tumor cells followed by treatment with a well characterizedimmunogenic peptide (e.g. TRP-2; SVYDFFVWL) expressed by the tumor cells(Ji, et al., J. Immunol, 2005, 175:1456-63). Importantly, immune systemmodifiers, such as anti-CTL-4 antibody, can improve responses to suchtherapeutic immunizations. The impact of IDO inhibitors may be evaluatedin a similar manner tumor peptide immunization with or without IDOinhibitor. Efficacy is assess by animal survival (time to morbididity)or by the measurement of tumor metastases to the lungs and/or otherorgans at defined timepoints.

In any/all of the above mentioned models, it may also be possible todirectly and/or indirectly measure the number and/or activity of tumorreative immune cells. Methods for measuring the number and/or activityof tumor reactive immune cells are well established and can be performedusing techniques familiar to those schooled in the art (CurrentProtocols in Immunology, vol 4, Coligan, J. E., et al; Immunotherapy ofCancer, Human Press, 2006, Disis, M. L. and references therein).Conceptually, a reduction in the immune suppressive effects of IDO mayresult in increased numbers or reactivity of tumor specific immunecells. Further, IDO inhibition may further increase the number orreactivity of tumor reactive immune cells when combined with othertherapeutics, for example chemotherapeutics and/or immune modulators(e.g. anti-CTLA4 antibody).

All allograft/xenograft experiments can be performed using standardtumor techniques (reviewed by Corbett, et al). The cloning andintroduction of genes (e.g. IDO, GM-CSF) into tumor cell lines, can beperformed using techniques familiar to those schooled in the art(reviewed in Sambrook, J, et al). See: Corbett, T., Polin, L., et al. Invivo methods for screening and preclinical testing. Cancer DrugDiscovery and Development: Anticancer Drug Development Guide:Preclinical Screening, Clinical Trials, and Approval, 2^(nd) Ed.Teicher, B. A. and Andrews, P. A., Gumana Press Inc., Totowa, N. J.,2004; Dranoff, G., Jaffee, E., et al. Vaccination with irradiated tumorcells engineered to secrete murine granulocyte-macrophagecolony-stimulating factor stimulates potent, specific, and long-lastinganti-tumor immunity. Proc. Natl. Acad. Sci, USA. 90:3539-3543, 1993;Friberg, M., Jennings, R., et al. Indoleamine 2,3-dioxygenasecontributes to tumor cell evasion of T cell-mediated rejection. Int. J.Cancer: 101:151-155, 2002; Muller, A. J., DuHadaway, J. B., et al.Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target ofthe cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat.Med. 11:312-319, 2005; Sambrook, J, Russel, D. Molecular Cloning: Alaboratory Manual (3^(rd) edition). Cold Spring Harbor Laboratory Press.Cold Spring Harbor, N.Y., USA. 2001; and Uyttenhove, C., Pilotte, L., etal. Evidence for a tumoral immune resistance mechanism based ontryptophan degradation by indoleamine 2,3-dioxygenase. Nat. Med.9:1269-1274, 2003.

Example E In Vivo Testing of IDO Inhibitors in Human ImmunodeficiencyVirus-1 (HIV-1) Encephalitis Model 1. Cell Isolation and Viral Infection

Monocytes and PBL can be obtained by countercurrent centrifugalelutriation of leukopheresis packs from HIV-1, 2 and hepatitis Bseronegative donors. Monocytes are cultivated in suspension cultureusing Teflon flasks in Dulbecco's Modififed Eagle's Medium (DMEM,Sigma-Aldrich) supplemented with 10% heat-inactivated pooled humanserum, 1% glutamine, 50 μg/mL gentamicin, 10 μg/mL ciprofloxacin(Sigma), and 1000 U/mL highly purified recombinant human macrophagecolony stimulating factor. After seven days in culture, MDM are infectedwith HIV-1_(ADA) at multiplicity of infection of 0.01.

2. Hu-PBL-NOD/SCID HIVE Mice

Four-wk old male NOD/C.B-17 SCID mice can be purchased (JacksonLaboratory). Animals are maintained in sterile microisolator cages underpathogen-free conditions. All animals are injected intraperitoneallywith rat anti-CD122 (0.25 mg/mouse) three days before PBLtransplantation and twice with rabbit asialo-GM1 antibodies (0.2mg/mouse) (Wako) one day before and three days after PBL injection(20×10⁶ cells/mouse). HIV-1_(ADA)-infected MDM (3×10⁵ cells in 10 μL)are injected intracranially (i.c.) eight days following PBLreconstitution generating hu-PBL-NOD/SCID HIVE mice. Immediatelyfollowing i.c. injection of HIV-1 infected MDM the hu-PBL-NOD/SCID HIVEmice are subcutaneously (s.c) implanted with control (vehicle) orcompound pellets (14 or 28 day slow release, Innovative Research).Initial experiments are designed to confirm the induction ofvirus-specific CTL in the hu PBL-NOD/SCID HIVE animals treated with IDOcompounds. This is confirmed by tetramer staining and neuropathologicanalyses of MDM elimination from the brain tissue. Then, the experimentis designed to analyze human lymphocyte reconstitution, humoral immuneresponses, and neuropathological alterations. In these experiments,animals are bled on day 7 and sacrificed at 14 and 21 days after i.c.injection of human MDM. Blood collected in EDTA-containing tubes is usedfor flow cytometry and plasma is used for detection of HIV-1 p24 usingELISA (Beckman Coulter™). HIV-1-specific antibodies are detected byWestern blot tests according to the manufacturer instructions (CambridgeBiotech HIV-1 Western blot kit, Calypte Biomedical). Similar amount ofvirus-specific antibodies are detected in control and compound-treatedanimals. A total of three independent experiments can be performed usingthree different human leukocyte donors.

3. FACScan of Peripheral Blood and Spleen in hu PBL-NOD/SCID HIVE Mice

Two-color FACS analysis can be performed on peripheral blood at wk 1-3and splenocytes at wk 2 and 3 after i.c. injection of human MDM. Cellsare incubated with fluorochrome-conjugated monoclonal Abs (mAbs) tohuman CD4, CD8, CD56, CD3, IFN-γ (eBioscience) for 30 min at 4° C. Toevaluate the cellular immune response, IFN-γ intracellular staining isperformed in combination with anti-human CD8 and FITC-conjugatedanti-mouse CD45 to exclude murine cells. To determine the Ag-specificCTL, allophycocyanin-conjugated tetramer staining for HIV-1^(gag) (p17(aa77-85) SLYNTVATL, SL-9) and HIV-1^(pol) [(aa476-485) ILKEPVHGV, IL-9]is performed on phytohemaglutinin/interleukin-2 (PHA/IL-2)-stimulatedsplenocytes. Cells are stained following the recommendation of theNIH/National Institute of Allergy and Infections Disease, NationalTetramer Core Facilities. Data were analyzed with a FACS Calibur™ usingCellQuest software (Becton Dickinson Immunocytometry System).

4. Histopathology and Image Analyses

Brain tissue is collected at days 14 and 21 after i.c. injection of MDM,fixed in 4% phosphate-buffered paraformaldehyde and embedded in paraffinor frozen at −80° C. for later use. Coronal sections from the embeddedblocks are cut in order to identify the injection site. For each mouse,30-100 (5-μm-thick) serial sections are cut from the human MDM injectionsite and 3-7 slides (10 sections apart) are analyzed. Brain sections aredeparaffinized with xylene and hydrated in gradient alcohols.Immunohistochemical staining follows a basic indirect protocol, usingantigen retrieval by heating to 95° C. in 0.01 mol/L citrate buffer for30 min for antigen retrieval. To identify human cells in mouse brains,mAb to vimentin (1:50, clone 3B4, Dako Corporation), which identifiesall human leukocytes is used. Human MDM and CD8⁺ lymphocytes aredetected with CD68 (1:50 dilution, clone KP 1) and CD8 (1:50 dilution,clone 144B) antibodies, respectively. Virus-infected cells are labeledwith mAb to HIV-1 p24 (1:10, clone Kal-1, all from Dako). Reactivemurine microglial cells are detected with Iba-1 antibody (1:500, Wako).Expression of human IDO (huIDO) is visualized with Abs obtained from theDepartment of Cell Pharmacology, Central Research Institute, GraduateSchool of Medicine, Hokkaido University, Sapporo, Japan. Primaryantibodies are detected with the appropriate biotinylated secondaryantibodies and visualized with avidin-biotin complexes (Vectastain EliteABC kit, Vector Laboratories) and horseradish peroxidase (HRP) coupleddextran polymer (EnVision, Dako Corporation). Immunostained sections arecounterstained with Mayer's hematoxylin. Sections from which primaryantibody is deleted or irrelevant IgG isotype is incorporated served ascontrols. Two independent observers in a blinded fashion count thenumbers of CD8⁺ lymphocytes, CD68⁺ MDM and HIV-1 p24⁺ cells in eachsection from each mouse. Light microscopic examination is performed witha Nikon Eclipse 800 microscope (Nikon Instruments Inc).Semi-quantitative analysis for Iba1 (percentage of area occupied byimmunostaining) is carried out by computer-assisted image analysis(Image-Pro®Plus, Media Cybernetics) as previously described.

5. Statistic Analysis

Data can be analyzed using Prism (Graph Pad) with Student t-test forcomparisons and ANOVA. P-values<0.05 were considered significant.

6. Reference

-   Poluektova L Y, Munn D H, Persidsky Y, and Gendelman H E (2002).    Generation of cytotoxic T cells against virus-infected human brain    macrophages in a murine model of HIV-1 encephalitis. J. Immunol.    168(8):3941-9.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound of Formula I:

or pharmaceutically acceptable salt form or prodrug thereof, wherein:Ring A is carbocyclyl or heterocyclyl optionally substituted by 1, 2, 3,4 or 5 R⁶; W, X¹, X², Y¹, and Y² are independently selected from(CR^(a)R^(b))_(t), (CR^(a)R^(b))_(u)O(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)NR(CR^(a)R^(b)),(CR^(a)R^(b))_(u)C(O)O(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(S)(CR^(a)R^(b))_(u),(CR^(a)R^(b))_(u)C(S)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)₂(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)₂NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)NR^(c)(CR^(a)R^(b))_(v), and(CR^(a)R^(b))_(u)C(═NR^(d))NR^(c)(CR^(a)R^(b))_(v); R¹ is H, C(O)R⁷,C(O)NR^(8a)R^(8b), C(O)OR⁸, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, or heterocycloalkylalkyl; R² is H,C₁₋₆ alkyl, or C₃₋₇ cycloalkyl; R^(3a), R^(4a), and R^(5a) areindependently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy¹, CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); R^(3b), R^(4b),and R^(5b) are independently selected from H, C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, eachoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂, OR^(e1), SR^(e1),C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); or R² and—(R^(3a))_(a)—(W)_(b)—R^(3b) together with the N atom to which they areattached form a 4- to 20-membered heterocycloalkyl group optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy³, CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), or S(O)₂NR^(g1)R^(h1); or—(Y¹)_(q)—(R^(4a))_(r)—(Y²)_(s)—R^(4b) and—(X¹)_(m)—(R^(5a))—(X²)_(p)—R^(5b) ether with the N atom to which theyare attached form a 4- to 20-membered heterocycloalkyl group optionallysubstituted by 1, 2, 3, 4 or 5 substituents selected from halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy⁴, CN, NO₂,OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); R⁶ is halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl,heterocycloalkylalkyl, CN, NO₂, OR^(e2), SR^(e2), C(O)R^(f2),C(O)NR^(g2)R^(h2), C(O)OR², OC(O)R^(f2), OC(O)NR^(g2)R^(h2),NR^(g2)R^(h2), NR^(g2)C(C)R^(f2), NR^(g2)C(O)OR^(e2),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f2))₂,P(OR^(e2))₂, P(O)R^(e2)R^(f2), P(O)OR^(e2)OR^(f2), S(O)R^(f2),S(O)NR^(g2)R^(h2), S(O)₂R^(f2), or S(O)₂NR^(g2)R^(h2); R⁷ and R⁸ areindependently selected from H, C₁₋₈ alkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, each optionally substituted by one or moresubstitutents independently selected from halo, CN, NO₂, OH, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino, C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; R^(8a) and R^(8b) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, and cycloalkylalkyl; Cy¹,Cy², Cy³, and Cy⁴ are independently selected from aryl, heteroaryl,cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2,3, 4 or 5 substituents independently selected from halo, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(e3), SR^(e3),C(O)R¹³, C(O)NR^(g3)R^(h3), C(O)OR^(e3), OC(O)R^(f3),OC(O)NR^(g3)R^(h3), NR^(g3)R^(h3), NR^(g3)C(O)R^(h3),NR^(g3)C(O)OR^(e3), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f3))₂, P(OR^(e3))₂,P(O)R^(e3)R^(f3), P(O)OR^(e3)OR^(f3), S(O)R^(f3), S(O)NR^(g3)R^(h3),S(O)₂R^(f3), and S(O)₂NR^(g3)R^(h3); R^(a) and R^(b) are independentlyselected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂,OR^(e4), SR^(e4), C(O)R^(f4), C(O)NR^(g4)R^(h4), C(O)OR^(e4),OC(O)R^(f4), OC(O)NR^(g4)R^(h4), NR^(g4)R^(h4), NR^(g4)C(O)R^(h4),NR^(g4)C(O)OR^(e4), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f4))₂, P(OR^(e4))₂,P(O)R^(e4)R^(f4), P(O)OR^(e4)OR^(f4), S(O)R^(f4), S(O)NR^(g4)R^(h4),S(O)₂R^(f4), and S(O)₂NR^(g4)R^(h4); R^(c) is H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl; R^(d) is H, OR^(d1), CN or NO₂; R^(d1) is H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,arylalkyl, or cycloalkylalkyl; R^(e1), R^(e2), R^(e3), and R^(e4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,(C₁₋₆ alkoxy)-C₁₋₆ alkyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl andheterocycloalkylalkyl; R^(f1), R^(f2), R^(f3), and R^(f4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl; R^(g1),R^(g2), R^(g3), and R^(g4) are independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,arylalkyl, and cycloalkylalkyl; R^(h1), R^(h2), R^(h3) and R^(h4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, and cycloalkylalkyl; orR^(g1) and R^(h1) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group; or R^(g2) andR^(h2) together with the N atom to which they are attached form a 4-,5-, 6- or 7-membered heterocycloalkyl group; or R^(g3) and R^(h3)together with the N atom to which they are attached form a 4-, 5-, 6- or7-membered heterocycloalkyl group; or R^(g4) and R^(h4) together withthe N atom to which they are attached form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group; R^(i) is H, CN, or NO₂; a is 0 or 1; b is 0 or1; m is 0 or 1; n is 0 or 1; p is 0 or 1; q is 0 or 1; r is 0 or 1; s is0 or 1; t is 1, 2, 3, 4, 5 or 6; u is 0, 1, 2, 3, 4, 5 or 6; and v is 0,1, 2, 3, 4, 5 or 6; with the provisos: a) when Ring A is

R² is H; —(Y¹)_(q)—(R^(4a))_(r)—(Y²)_(s)—R^(4b) is H; and—(X¹)_(m)—(R^(5a))_(n)—(X²)_(p)—R^(5b) is H; then—(R^(3a))_(a)—(W)—R^(3b) is other than: i) phenyl, 4-iodophenyl,4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 3-methylphenyl,2-methylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl,2,5-dimethylphenyl, 3,4-dimethylphenyl, 2-methoxyphenyl, or2-dimethylamino-5-nitrophenyl; ii) —CH₂CH₂NR^(x)R^(y), wherein eachR^(x) and R^(y) is, independently, H, ethyl, —C(O)-oxadiazole optionallysubstituted with amino, or phenyl optionally having at least onesubstituent which is nitro; or iii) C₁₋₃ alkyl, —C(O)—(C₁₋₄ haloalkyl),naphthyl, or benzyl; b) when Ring A is phenyl having at least twosubstituents which are methyl; —(Y¹)_(q)—(R^(4a))_(r)—(Y²)_(s)—R^(4b) isH; and —(X¹)_(m)—(R^(5a))_(n)—(X²)_(p)—R^(5b) is H; then—(R^(3a))_(a)—(W)—R^(3b) is other than unsubstituted phenyl; and c) whenRing A is phenyl having at least one substitutent which is nitro;—(Y¹)_(q)—(R^(4a))_(r)—(Y²)_(s)—R^(4b) is H; and—(X¹)_(m)—(R^(5a))_(n)—(X²)_(p)—R^(5b) is H; then—(R^(3a))_(a)—(W)—R^(3b) is other than pyrazolyl substituted by C₁₋₄alkyl.
 2. The compound of claim 1 wherein Ring A is heterocyclyloptionally substituted by 1, 2, 3, 4 or 5 R⁶.
 3. The compound of claim 1wherein Ring A is 5- or 6-membered heterocyclyl optionally substitutedby 1, 2, 3, 4 or 5 R⁶.
 4. The compound of claim 1 wherein Ring A is5-membered heterocyclyl optionally substituted by 1, 2, 3, 4 or 5 R⁶. 5.The compound of claim 1 wherein Ring A is 5-membered heterocyclylcontaining at least one ring-forming N atom and Ring A is optionallysubstituted by 1, 2, 3, 4 or 5 R⁶.
 6. The compound of claim 1 whereinRing A is 5-membered heterocyclyl containing at least one ring-forming Oatom and Ring A is optionally substituted by 1, 2, 3, 4 or 5 R⁶.
 7. Thecompound of claim 1 wherein Ring A is 5-membered heterocyclyl containingat least one ring-forming O atom and containing at least onering-forming N atom, and Ring A is optionally substituted by 1, 2, 3, 4or 5 R⁶.
 8. The compound of claim 1 wherein Ring A is


9. The compound of claim 1 wherein Ring A is


10. The compound of claim 1 wherein R¹ is H, C(O)R⁷, C(O)NR^(8a)R^(8b),or C(O)OR⁸.
 11. The compound of claim 1 wherein R¹ is H.
 12. Thecompound of claim 1 wherein R² is H.
 13. The compound of claim 1 whereina and b are both
 0. 14. The compound of claim 1 wherein R^(3b) is aryl,cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substitutedby 1, 2, 3, 4 or 5 substituents independently selected from halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl,Cy², CN, NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1),C(O)OR^(e1), OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)R^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).
 15. The compoundof claim 1 wherein R^(3b) is aryl or heteroaryl each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, Cy², CN, NO₂, OR^(e1), SR^(e1), C(O)R^(f1),C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1), OC(O)NR^(g1)R^(h1),NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1), NR^(g1)C(O)R^(f1),NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).
 16. The compound of claim 1 whereinR^(3b) is phenyl optionally substituted by 1, 2, 3, 4 or 5 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂, OR^(e1),SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).
 17. The compound of claim 1 whereinr and s are both
 0. 18. The compound of claim 1 wherein q, r, and s areall
 0. 19. The compound of claim 1 wherein Y¹ is (CR^(a)R^(b))_(t) or(CR^(a)R^(b))_(u)C(O)(CR^(a)R^(b))_(v).
 20. The compound of claim 1wherein R^(4b) is H.
 21. The compound of claim 1 wherein n and p areboth
 0. 22. The compound of claim 1 wherein X¹ is (CR^(a)R^(b))_(t),(CR^(a)R^(b))_(u)C(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)NR^(c)(CR^(a)R^(b))_(v), or(CR^(a)R^(b))_(u)C(O)O(CR^(a)R^(b))_(v).
 23. The compound of claim 1wherein R^(5b) is H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substitutedby 1, 2, 3, 4 or 5 substituents independently selected from halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl,Cy², CN, NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1),C(O)OR^(e1), OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(═NR^(i))NR^(g)R^(h1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).
 24. The compoundof claim 1 wherein R^(4b) is H and R^(5b) is H, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂, OR^(e1),SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).
 25. The compound of claim 1 wherein—(Y¹)_(q)—(R^(4a))_(r)—(Y²)_(s)—R^(4b) is H and—(X¹)_(m)—(R^(5a))—(X²)_(p)—R^(5b) is H.
 26. A compound of claim 1having Formula II:

or pharmaceutically acceptable salt form or prodrug thereof, wherein: X¹is (CR^(a)R^(b))_(t) or (CR^(a)R^(b))_(u)C(O)(CR^(a)R^(b))_(v); R^(3a)is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, cycloalkyl, heteroaryl,or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, Cy¹, CN, NO₂, OR^(e1),SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1), R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); R^(3b) is H, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂, OR^(e1),SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)R^(h1), NR^(g1)C(O)R^(f1),NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); R^(5b) and R^(b) is H, C₁₋₈ alkyl,C₂₋₄ alkenyl, C₂₋₈ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂, OR^(e1),SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)R^(h1), NR^(g1)C(O)R^(f1),NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); Cy¹ and Cy² are independentlyselected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, eachoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, CN, NO₂, OR^(e3), SR^(e3), C(O)R^(f3), C(O)NR^(g3)R^(h3),C(O)OR^(e3), OC(O)R^(f3), OC(O)NR^(g3)R^(h3), NR^(g3)R^(h3),NR^(g3)C(O)R^(h3), NR^(g3)C(O)OR^(e3), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f3))₂, P(OR^(e3))₂,P(O)R^(e3)R^(f3), P(O)OR^(e3)R^(f3), S(O)R^(f3), S(O)NR^(g3)R^(h3),S(O)₂R^(f3), and S(O)₂NR^(g3)R^(h3); R^(a) and R^(b) are independentlyselected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂,OR^(e4), SR^(e4), C(O)R^(f4), C(O)NR^(g4)R^(h4), C(O)OR^(e4),OC(O)R^(f4), OC(O)NR^(g4)R^(h4), NR^(g4)R^(h4), NR^(g4)C(O)R^(h4),NR^(g4)C(O)OR^(e4), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f4))₂, P(OR^(e4))₂,P(O)R^(e4)R^(e4), P(O)OR^(e4)R^(e4), S(O)R^(f4), S(O)NR^(g4)R^(h4),S(O)₂R^(f4), and S(O)₂NR^(g4)R^(h4); R^(e1), R^(e3), and R^(e4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,(C₁₋₆ alkoxy)-C₁₋₆ alkyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl andheterocycloalkylalkyl; R^(f1), R^(f3), and R^(f4) are independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl and heterocycloalkyl; R^(g1), R^(g3), andR^(g4) are independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, andcycloalkylalkyl; R^(h1), R^(h3), and R^(h4) are independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, arylalkyl, and cycloalkylalkyl; or R^(g1) and R^(h1)together with the N atom to which they are attached form a 4-, 5-, 6- or7-membered heterocycloalkyl group; or R^(g3) and R^(h3) together withthe N atom to which they are attached form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group; or R^(g4) and R^(h4) together with the N atom towhich they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup; R^(i) is H, CN, or NO₂; a is 0 or 1; m is 0 or 1; t is 1, 2, 3,4, 5 or 6; u is 0, 1, 2, 3, 4, 5 or 6; and v is 0, 1, 2, 3, 4, 5 or 6;with the provisos: a) when —(X¹)_(m)—R^(5b) is H; then—(R^(3a))_(a)—R^(3b) is other than: i) phenyl, 4-iodophenyl,4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 3-methylphenyl,2-methylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl,2,5-dimethylphenyl, 3,4-dimethylphenyl, 2-methoxyphenyl, or2-dimethylamino-5-nitrophenyl; ii) —CH₂CH₂NR^(x)R^(y), wherein eachR^(x) and R^(y) is, independently, H, ethyl, —C(O)-oxadiazole optionallysubstituted with amino, or phenyl optionally having at least onesubstituent which is nitro; or iii) C₁₋₃ alkyl, —C(O)—(C₁₋₄ haloalkyl),naphthyl, or benzyl.
 27. The compound of claim 26 wherein R^(3a) is C₁₋₈alkyl.
 28. The compound of claim 26 wherein R^(3b) is aryl heteroaryl,each optionally substituted by 1, 2, 3, 4 or 5 substituentsindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂, OR^(e1),SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)R^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).
 29. The compound of claim 26wherein R^(5b) is H, aryl, or heteroaryl, each optionally substituted by1, 2, 3, 4 or 5 substituents independently selected from halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl,Cy², CN, NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1),C(O)OR^(e1), OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)R^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1).
 30. A compoundof Formula I:

or pharmaceutically acceptable salt form or prodrug thereof, wherein:Ring A is a 5-membered carbocyclyl or heterocyclyl ring optionallysubstituted by 1, 2, 3, 4 or 5 R⁶; W, X¹, X², Y¹, and Y² areindependently selected from (CR^(a)R^(b))_(t),(CR^(a)R^(b))_(u)O(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)O(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(S)(CR^(a)R^(b))_(u),(CR^(a)R^(b))_(u)C(S)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)₂(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)₂NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)NR^(c)(CR^(a)R^(b))_(v), and(CR^(a)R^(b))_(u)C(═NR^(d))NR^(c)(CR^(a)R^(b))_(v); R¹ is H, C(O)R⁷,C(O)NR^(8a)R^(8b), C(O)OR⁸, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, or heterocycloalkylalkyl; R² is H,C₁₋₆ alkyl, or C₃₋₇ cycloalkyl; R^(3a), R^(4a), and R^(5a) areindependently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy¹, CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); R^(3b) is H,C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂, OR^(e1),SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)R^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); R^(4b) is H; R^(5b) is C₁₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂, OR^(e1),SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)R^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); or R² and—(R^(3a))_(a)—(W)_(b)—R^(3b) together with the N atom to which they areattached form a 4- to 20-membered heterocycloalkyl group optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy³, CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂e, and S(O)₂NR^(g1)R^(h1); or—(Y¹)_(q)—(R^(4a))_(r)—(Y²)_(s)—R^(4b) and—(X¹)_(m)—(R^(5a))_(n)—(X²)_(p)—R^(5b) together with the N atom to whichthey are attached form a 4- to 20-membered heterocycloalkyl groupoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄haloalkyl, Cy⁴, CN, NO₂, OR^(e1), SR^(e1), C(O)R^(f1),C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1), OC(O)NR^(g1)R^(h1),NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1), NR^(g1)C(O)R^(f1),NR^(g1)C(O)OR^(e1), S(O)R^(f1), S(O)NR^(g1)R^(h1), S(O)₂R^(f1), andS(O)₂NR^(g1)R^(h1); R⁶ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN,NO₂, OR^(e2), SR^(e2), C(O)R^(f2), C(O)NR^(g2)R^(h2), C(O)OR^(e2),OC(O)R^(f2), OC(O)NR^(g2)R^(h2), NR^(g2)R^(h2), NR^(g2)C(O)R^(f2),NR^(g2)C(O)OR^(e2), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f2))₂, P(OR^(e2))₂,P(O)R^(e2)R^(f2), P(O)OR^(e2)OR^(f2), S(O)R^(f2), S(O)NR^(g2)R^(h2),S(O)₂R^(f2), or S(O)₂NR^(g2)R^(h2); R⁷ and R⁸ are independently selectedfrom H, C₁₋₈ alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,each optionally substituted by one or more substituents independentlyselected from halo, CN, NO₂, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino,C₁₋₄ alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl; R^(8a) and R^(8b) are independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,arylalkyl, and cycloalkylalkyl; Cy¹, Cy², Cy³, and Cy⁴ are independentlyselected from aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, eachoptionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, CN, NO₂, OR^(e3), SR^(e3), C(O)R^(f3), C(O)NR^(g3)R^(h3),C(O)OR^(e3), OC(O)R^(f3), OC(O)NR^(g3)R^(h3), NR^(g3)R^(h3),NR^(g3)C(O)R^(h3), NR^(g3)C(O)OR^(e3), S(O)R^(f3), S(O)NR^(g3)R^(h3),S(O)_(2R) ^(f3), and S(O)₂NR^(g3)R^(h3); R^(a) and R^(b) areindependently selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN,NO₂, OR^(e4), SR^(e4), C(O)R^(f4), C(O)N^(g4)R^(h4), C(O)OR^(e4),OC(O)R^(f4), OC(O)NR^(g4)R^(h4), NR^(g4)R^(h4), NR^(g4)C(O)R^(h4),NR^(g4)C(O)OR^(e4), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f4))₂, P(OR^(e4))₂,P(O)R^(e4)R^(f4), P(O)OR^(e4)OR^(f4), S(O)R^(f4), S(O)NR^(g4)R^(h4),S(O)₂R^(f4), and S(O)₂NR^(g4)R^(h4); R^(c) is H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl; R^(d) is H, OR^(d1), CN or NO₂; R^(d1) is H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,arylalkyl, or cycloalkylalkyl; R^(e1), R^(e2), R^(e3), and R^(e4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,(C₁₋₆ alkoxy)-C₁₋₆ alkyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl orheterocycloalkylalkyl; R^(f1), R^(f2), R^(f3), and R^(f4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; R^(g1),R^(g2), R^(g3), and R^(g4) are independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,arylalkyl, or cycloalkylalkyl; R^(h1), R^(h2), R^(h3), and R^(h4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; or R^(g1)and R^(h1) together with the N atom to which they are attached form a4-, 5-, 6- or 7-membered heterocycloalkyl group; or R^(g2) and R^(h2)together with the N atom to which they are attached form a 4-, 5-, 6- or7-membered heterocycloalkyl group; or R^(g3) and R^(h3) together withthe N atom to which they are attached form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group; or R^(g4) and R^(h4) together with the N atom towhich they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup; R^(i) is H, CN, or NO₂; a is 0 or 1; b is 0 or 1; m is 0 or 1; nis 0 or 1; p is 0 or 1; q is 0; r is 0; s is 0; t is 1, 2, 3, 4, 5 or 6;u is 0, 1, 2, 3, 4, 5 or 6; and v is 0, 1, 2, 3, 4, 5 or
 6. 31. Acompound of claim 1 selected from:4-Amino-N-(3-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-phenyl-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(2-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(4-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(4-bromophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-(2-methylphenyl)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-(3-methylphenyl)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-(4-methylphenyl)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-[3-(trifluoromethyl)phenyl]-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-(2-methoxyphenyl)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-(3-methoxyphenyl)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-(4-methoxyphenyl)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-[3-(benzyloxy)phenyl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-(3-Acetylphenyl)-4-amino-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-cyanophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3,4-difluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(4-bromo-3-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-chloro-4-methylphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3,4-dimethylphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-[4-(benzyloxy)-3-chlorophenyl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-benzyl-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(2-fluorobenzyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(2-chlorobenzyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-chlorobenzyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(4-chlorobenzyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-[3-(trifluoromethyl)benzyl]-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-(2-methoxybenzyl)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-(pyridin-2-ylmethyl)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-(2-phenylethyl)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-1H-indol-5-yl-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-butyl-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-{4-[[(3-Chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-phenylacetamide;N-{4-[[(3-Chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}benzamide;N-{4-[(Benzylamino)(hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}benzamide;N-benzyl-4-(benzylamino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-[(Anilinocarbonyl)amino]-N-(3-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-[Bis(anilinocarbonyl)amino]-N-(3-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;tert-Butyl{4-[({4-[(E,Z)-[(3-chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}amino)carbonyl]benzyl}carbamate;4-(Aminomethyl)-N-{4-[(E,Z)-[(3-chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}benzamide;4-{[(Benzylamino)carbonyl]amino}-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-thiadiazole-3-carboximidamide;4-Amino-N-(6-chloropyridin-2-yl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-bromo-4-fluorophenyl)-N′-hydroxyisothiazole-3-carboximidamide;4-Amino-N-(2,5-dichlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}morpholine-4-carboxamide;N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-(methylamino)-1,2,5-oxadiazole-3-carboximidamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}piperidine-4-carboxamide;tert-Butyl4-{4-[({4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}amino)carbonyl]benzyl}piperazine-1-carboxylate;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-(piperazin-1-ylmethyl)benzamide;1-Benzoyl-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}piperidine-4-carboxamide;N(4)-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-N(1)-phenylpiperidine-1,4-dicarboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1-ethylpiperidine-4-carboxamide;4-[(Benzoylamino)methyl]-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}benzamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(2-cyanophenoxy)acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-phenylpiperidine-4-carboxamide;N-(3-Bromo-4-fluorophenyl)-4-({-4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzyl}amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-{[4-(morpholin-4-ylmethyl)benzyl]amino}-1,2,5-oxadiazole-3-carboximidamide;N-(3-Cyano-4-fluorophenyl)-4-({-4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzyl}amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-[(pyridin-3-ylmethyl)amino]-1,2,5-oxadiazole-3-carboximidamide;N-(3-Cyano-4-fluorophenyl)-N′-hydroxy-4-[(pyridin-4-ylmethyl)amino]-1,2,5-oxadiazole-3-carboximidamide;4-[(3-Cyanobenzyl)amino]-N-(3-cyano-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-[(1H-tetrazol-5-ylmethyl)amino]-1,2,5-oxadiazole-3-carboximidamide;N′-(Acetyloxy)-4-amino-N-(3-chloro-4-fluorophenyl)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-(3-chloro-4-fluorophenyl)-N′-(propionyloxy)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-{[(benzylamino)carbonyl]oxy}-N-(3-chloro-4-fluorophenyl)-1,2,5-oxadiazole-3-carboximidamide;N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-morpholin-4-yl-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-[3-(3-hydroxyprop-1-yn-1-yl)phenyl]-1,2,5-oxadiazole-3-carboximidamide;N-{4-[(E,Z)-[(3-Chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}cyclopentanecarboxamide;N-{4-[(E,Z)-[(3-Chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}nicotinamide;N-{4-[(E,Z)-[(3-Chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}isonicotinamide;N-{4-[(E,Z)-[(3-Chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-methoxybenzamide;N-{4-[(E,Z)-[(3-Chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-methoxybenzamide;N-{4-[(E,Z)-[(3-Chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-methoxybenzamide;2-Chloro-N-{4-[(E,Z)-[(3-chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}benzamide;3-Chloro-N-{4-[(E,Z)-[(3-chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}benzamide;4-Chloro-N-{4-[(E,Z)-[(3-chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}benzamide;N-{4-[(E,Z)-[(3-Chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3,3-dimethylbutanamide;4-Amino-N-(3-bromophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-bromo-4-methylphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-chloro-4-methoxyphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3,5-dimethyl-phenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-(2-methylbenzyl)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-(3-methylbenzyl)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-(4-methylbenzyl)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-[2-(trifluoromethyl)benzyl]-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-[4-(trifluoromethyl)benzyl]-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-ethyl-phenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3,4-dichlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3,5-dichlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-biphenyl-3-yl-N-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(2-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-chloro-4-methylbenzyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(2,3-dimethylphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-{4-[(E,Z)-[(3-Chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-iodobenzamide;4-Amino-N-(4-chloro-3-methylphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-[3-(methylthio)phenyl]-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-chloro-2-methylphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-fluoro-2-methylphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-(3-vinylphenyl)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-ethynylphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(4-fluoro-3-methylphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-(3-iodophenyl)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-(3-isopropylphenyl)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-(4-phenylbutyl)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-[3-(1,3-oxazol-5-yl)phenyl]-1,2,5-oxadiazole-3-carboximidamide;N-{4-[(E,Z)-[(3-Chlorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-cyanobenzamide;4-Amino-N′-hydroxy-N-[1-phenylethyl]-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-1-naphthyl-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-2-naphthyl-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-chloro-2-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-{4-[(E,Z)-{[4-Fluoro-3-(trifluoromethyl)phenyl]amino}(hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}nicotinamide;N-{4-[(E,Z)-{[4Fluoro-3-(trifluoromethyl)phenyl]amino}(hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}isonicotinamide;4-Amino-N-(3-cyclopropylphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}benzamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}isonicotinamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}isonicotinamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-cyanobenzamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-cyanobenzamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-naphthamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1-naphthamide;1-Acetyl-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}piperidine-4-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-furamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}thiophene-2-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;4-(Acetylamino)-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}benzamidetert-Butyl{4-[({4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}amino)carbonyl]benzyl}carbamateN-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1-benzothiophene-2-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1,3-thiazole-4-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1-benzothiophene-3-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}thiophene-3-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1H-imidazole-2-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-methyl-1,2,3-thiadiazole-5-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1,2,3-thiadiazole-4-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2,1-benzisoxazole-3-carboxamide;4-(Aminomethyl)-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}benzamide;N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-({[(2-phenylethyl)amino]carbonyl}amino)-1,2,5-oxadiazole-3-carboximidamide;N-(3-Bromo-4-fluorophenyl)-4-{[(cyclopentylamino)carbonyl]amino}-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-(3-Bromo-4-fluorophenyl)-4-({[(3-cyanophenyl)amino]carbonyl}amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-tert-butyl-1-methyl-1H-pyrazole-5-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-methoxyacetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}cyclopentanecarboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}butanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-methylpropanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}propanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}cyclohexanecarboxamide;4-Amino-N-(2,3-dichlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-chlorophenyl)-N′-hydroxy-N-methyl-1,2,5-oxadiazole-3-carboximidamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1H-benzimidazole-5-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-phenoxyacetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}cyclobutanecarboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-methylbutanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-pyridin-3-ylpropanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}quinoline-6-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(4-chlorophenoxy)acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(4-bromophenoxy)acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(4-fluorophenoxy)acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(4-tert-butylphenoxy)acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(3-chlorophenoxy)acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(3,4-dichlorophenoxy)acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(2-naphthyloxy)acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(2,3-dichlorophenoxy)acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(4-chlorophenoxy)-2-methylpropanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(2-chlorophenoxy)acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(3-methoxyphenoxy)acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(4-methoxyphenoxy)acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(2-methoxyphenoxy)acetamide;Benzyl{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}carbamate;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}piperidine-1-carboxamide;N-(3-Bromo-4-fluorophenyl)-4-({[(3-cyanophenyl)(methyl)amino]carbonyl}amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-(6-methylpyridin-2-yl)-1,2,5-oxadiazole-3-carboximidamide;4-({[Benzyl(methyl)amino]carbonyl}amino)-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-phenylacetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(3-methoxyphenyl)acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(4-methoxyphenyl)acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(2-methoxyphenyl)acetamide;4-Amino-N-(2,4-dichlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-cyanobenzamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-(3-bromophenyl)propanamide;N-{4-[(E,4-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-(4-bromophenyl)propanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-(4-chlorophenyl)propanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-(3-chlorophenyl)propanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}3-(2-fluorophenyl)propanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-(3-fluorophenyl)propanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-(2-chlorophenyl)propanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-(3-methylphenyl)propanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-(3-(trifluoromethyl)phenyl)propanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-(4-fluorophenyl)propanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-(2-methoxyphenyl)propanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-(3-methoxyphenyl)propanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-(4-methoxyphenyl)propanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-(4-methylphenyl)propanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-[4-(trifluoromethyl)phenyl]propanamide;3-[2,5-Bis(trifluoromethyl)phenyl]-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}propanamide;3-[3,5-Bis(trifluoromethyl)phenyl]-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}propanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-methyl-3-phenylpropanamide;2-Benzyl-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3,3-dimethylbutanamide;4-Amino-N-(5-chloro-2-methoxyphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(5-chloro-2-methylphenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(5-chloro-2-nitrophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(5-chloro-2-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidine-4-carboxamide;1-Benzyl-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-tert-butyl-1H-pyrazole-5-carboxamide;2-(Benzyloxy)-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1-(4-chlorophenyl)cyclopentanecarboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-phenoxybenzamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2,4,6-trichlorobenzamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-methoxybenzamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-methoxybenzamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2,2-diphenylacetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-(trifluoromethoxy)benzamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-methoxybenzamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3,4-dimethoxybenzamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(2-nitrophenoxy)acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-chloronicotinamidetrifluoroacetate;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}biphenyl-4-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(2,6-dichlorobenzyl)-1,3-thiazole-4-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2,6-dimethoxybenzamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-nitrobenzamide;5-Bromo-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}nicotinamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3}-3,3-dimethylbutanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(2-thienyl)acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-phenylbutanamide;4-Amino-N-(2-bromo-5-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2,2-dimethylpropanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-(morpholin-4-ylmethyl)benzamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-[(1,1-dioxidothiomorpholin-4-yl)methyl]benzamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1-(phenylacetyl)piperidine-4-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1-(methylsulfonyl)piperidine-4-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-pyridin-4-yl-1,3-thiazole-4-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-nitrobenzamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-nitrobenzamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1-isopropylpiperidine-4-carboxamide;tert-Butyl4-{4-[({4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}amino)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-phenyl-1,3-thiazole-4-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-methyl-1,3-thiazole-4-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-piperidin-4-yl-1,3-thiazole-4-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(4-cyanophenoxy)acetamide;tert-Butyl3-[({4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}amino)carbonyl]piperidine-1-carboxylate;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-3-(3-nitrophenyl)propanamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(3-nitrophenoxy)acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(4-nitrophenoxy)acetamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}piperidine-3-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-methyl-2-pyridin-3-yl-1,3-thiazole-5-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-methyl-1,3-thiazole-5-carboxamide;2-Amino-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1,3-thiazole-4-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-methyl-2-pyrazin-2-yl-1,3-thiazole-5-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2,4-dimethyl-1,3-thiazole-5-carboxamide;1-Acetyl-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}pyrrolidine-2-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1,5-dimethyl-1H-pyrazole-3-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-5-chloro-1-methyl-1H-pyrazole-4-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1,3-dimethyl-1H-pyrazole-5-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1-methyl-1H-imidazole-2-carboxamide;4-[(Acetylamino)methyl]-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}benzamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-methylpiperidine-4-carboxamide;1-Acetyl-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}piperidine-3-carboxamide;1-Acetyl-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-methylpiperidine-4-carboxamide;1-Acetyl-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-phenylpiperidine-4-carboxamide;4-(Benzylamino)-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-1-ethylpiperidine-3-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-4-ethylpiperazine-1-carboxamide;4-Acetyl-N-{4-[(E,Z)-[(3-bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}piperazine-1-carboxamide;N-{4-[(E,Z)-[(3-Bromo-4-fluorophenyl)amino](hydroxyimino)methyl]-1,2,5-oxadiazol-3-yl}-2-(1-ethylpiperidin-4-yl)-1,3-thiazole-4-carboxamide;4-Amino-N-(3-cyano-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-[(1,3-thiazol-4-ylmethyl)amino]-1,2,5-oxadiazole-3-carboximidamide;N-(3-Bromo-4-fluorophenyl)-4-[(4-cyanobenzyl)amino]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-chloro-5-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-[3-(difluoromethyl)phenyl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-{[(1-methylpiperidin-4-yl)methyl]amino}-1,2,5-oxadiazole-3-carboximidamide;N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-{[4-(piperazin-1-ylmethyl)benzyl]amino}-1,2,5-oxadiazole-3-carboximidamide;N-(3-Bromo-4-fluorophenyl)-4-({4-[(4-ethylpiperazin-1-yl)methyl]benzyl}amino)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-(3-hydroxyphenyl)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-chloro-4-fluorophenyl)-N′-(isobutyryloxy)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-chloro-4-fluorophenyl)-N′-[(3-methylbutanoyl)oxy]-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-(benzoyloxy)-N-(3-chloro-4-fluorophenyl)-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-chloro-4-fluorophenyl)-N′-[(2,2-dimethylpropanoyl)oxy]-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-[3-(cyanomethyl)phenyl]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N-(3-cyano-2-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-[3-(methoxymethyl)phenyl]-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-[3-(3-methoxyprop-1-yn-1-yl)phenyl]-1,2,5-oxadiazole-3-carboximidamide;4-Amino-N′-hydroxy-N-(2-methyl-1,3-benzoxazol-4-yl)-1,2,5-oxadiazole-3-carboximidamide;4-Anilino-N-(3-bromo-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide;N-(3-Bromo-4-fluorophenyl)-N′-hydroxy-4-[(pyridin-4-ylmethyl)amino]-1,2,5-oxadiazole-3-carboximidamide;andN-(3-Bromo-4-fluorophenyl)-4-[(3-cyanobenzyl)amino]-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide,or pharmaceutically acceptable salt thereof.
 32. A compositioncomprising a compound of Formula I:

or pharmaceutically acceptable salt form or prodrug thereof, wherein:Ring A is carbocyclyl or heterocyclyl optionally substituted by 1, 2, 3,4 or 5 R⁶; W, X¹, Y¹, and Y² are independently selected from(CR^(a)R^(b))_(t), (CR^(a)R^(b))_(u)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)O(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(S)(CR^(a)R^(b))_(u),(CR^(a)R^(b))_(u)C(S)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)₂(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)₂NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)NR^(c)(CR^(a)R^(b))_(v), and(CR^(a)R^(b))_(u)C(═NR^(d))NR^(c)(CR^(a)R^(b))_(v); R¹ is H, C(O)R⁷,C(O)NR^(8a)R^(8b), C(O)OR⁸, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, or heterocycloalkylalkyl; R² is H,C₁₋₆ alkyl, or C₃₋₇ cycloalkyl; R^(3a), R^(4a), and R^(5a) areindependently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy¹, CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); R^(3b), R^(4b),and R^(5b) are independently selected from H, C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, eachoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂, OR^(e1), SR^(e1),C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)R^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); or R² and—(R^(3a))_(a)—(W)_(b)—R^(3b) together with the N atom to which they areattached form a 4- to 20-membered heterocycloalkyl group optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy³, CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(O)NR^(g1)R^(h1), P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1),S(O)R^(f1), S(O)NR^(g1)R^(h1), S(O)₂R^(f1), or S(O)₂NR^(g1)R^(h1); or—(Y¹)_(q)—(R^(4a))_(r)—(Y²)_(s)—R^(4b) and—(X¹)_(m)—(R^(5a))_(n)—(X²)_(p)—R^(5b) together with the N atom to whichthey are attached form a 4- to 20-membered heterocycloalkyl groupoptionally substituted by 1, 2, 3, 4 or 5 substituents selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy⁴, CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(NR^(i))NR^(g1)R^(h1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); R⁶ is halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂, OR^(e2), SR^(e2),C(O)R^(f2), C(O)NR^(g2)R^(h2), C(O)OR^(e2), OC(O)R^(f2),OC(O)NR^(g2)R^(h2), NR^(g2)R^(h2), NR^(g2)C(O)R^(f2),NR^(g2)C(O)OR^(e2), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f2))₂, P(OR^(e2))₂,P(O)R^(e2)R^(f2), P(O)OR^(e2)OR^(f2), S(O)R^(f2), S(O)NR^(g2)R^(h2),S(O)₂R^(f2), or S(O)₂NR^(g2)R^(h2); R⁷ and R⁸ are independently selectedfrom H, C₁₋₈ alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,each optionally substituted by one or more substitutents independentlyselected from halo, CN, NO₂, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino,C₁₋₄ alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl; R^(8a) and R^(8b) are independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,arylalkyl, and cycloalkylalkyl; Cy¹, Cy², Cy³, and Cy⁴ are independentlyselected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, eachoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, CN, NO₂, OR^(e3), SR^(e3), C(O)R^(f3), C(O)NR^(g3)R^(h3),C(O)OR^(e3), OC(O)R^(f3), OC(O)NR^(g3)R^(h3), NR^(g3)R^(h3),NR^(g3)C(O)R^(h3), NR^(g3)C(O)OR^(e3), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f3))₂, P(OR^(e3))₂,P(O)R^(e3)R^(f3), P(O)OR^(e3)OR^(f3), S(O)R^(f3), S(O)NR^(g3)R^(h3),S(O)₂R^(f3), and S(O)₂NR^(g3)R^(h3); R^(a) and R^(b) are independentlyselected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂,OR^(e4), SR^(e4), C(O)R^(f4), C(O)NR^(g4)R^(h4), C(O)OR^(e4),OC(O)R^(f4), OC(O)NR^(g4)R^(h4), NR^(g4)R^(h4), NR^(g4)C(O)R^(h4),NR^(g4)C(O)OR^(e4), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f4))₂, P(OR^(e4))₂,P(O)R^(e4)R^(f4), P(O)OR^(e4)OR^(f4), S(O)R^(f4), S(O)NR^(g4)R^(h4),S(O)₂R^(f4), and S(O)₂NR^(g4)R^(h4); R^(c) is H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl; R^(d) is H, OR^(d1), CN or NO₂; R^(d1) is H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,arylalkyl, or cycloalkylalkyl; R^(e1), R^(e2), R^(e3), and R^(e4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,(C₁₋₆ alkoxy)-C₁₋₆ alkyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl andheterocycloalkylalkyl; R^(f1), R^(f2), R^(f3), and R^(f4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl; R^(g1),R^(g2), R^(g3), and R^(g4) are independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,arylalkyl, and cycloalkylalkyl; R^(h1), R^(h2), R^(h3), and R^(h4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, and cycloalkylalkyl; orR^(g1) and R^(h1) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group; or R^(g2) andR^(h2) together with the N atom to which they are attached form a 4-,5-, 6- or 7-membered heterocycloalkyl group; or R^(g3) and R^(h3)together with the N atom to which they are attached form a 4-, 5-, 6- or7-membered heterocycloalkyl group; or R^(g4) and R^(h4) together withthe N atom to which they are attached form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group; R^(i) is H, CN, or NO₂; a is 0 or 1; b is 0 or1; m is 0 or 1; n is 0 or 1; p is 0 or 1; q is 0 or 1; r is 0 or 1; s is0 or 1; t is 1, 2, 3, 4, 5 or 6; u is 0, 1, 2, 3, 4, 5 or 6; and v is 0,1, 2, 3, 4, 5 or 6; and a pharmaceutically acceptable carrier.
 33. Amethod of modulating activity of indoleamine 2,3-dioxygenase comprisingcontacting said indoleamine 2,3-dioxygenase with a compound of FormulaI:

or pharmaceutically acceptable salt form or prodrug thereof, wherein:Ring A is carbocyclyl or heterocyclyl optionally substituted by 1, 2, 3,4 or 5 R⁶; W, X¹, X², Y¹, and Y² are independently selected from(CR^(a)R^(b))_(t), (CR^(a)R^(b))_(u)O(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)O(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(S)(CR^(a)R^(b))_(u),(CR^(a)R^(b))_(u)C(S)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)₂(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)₂NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)NR^(c)(CR^(a)R^(b))_(v), and(CR^(a)R^(b))_(u)C(═NR^(d))NR^(c)(CR^(a)R^(b))_(v); R¹ is H, C(O)R⁷,C(O)NR^(8a)R^(8b), C(O)OR⁸, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, or heterocycloalkylalkyl; R² is H,C₁₋₆ alkyl, or C₃₋₇ cycloalkyl; R^(3a), R^(4a), and R^(5a) areindependently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy¹, CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); R^(3b), R^(4b),and R^(5b) are independently selected from H, C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, eachoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂, OR^(e1), SR^(e1),C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)R^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); or R² and—(R^(3a))_(a)—(W)_(b)—R^(3b) together with the N atom to which they areattached form a 4- to 20-membered heterocycloalkyl group optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy³, CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(O)NR^(g1)R^(h1), P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1),S(O)R^(f1), S(O)NR^(g1)R^(h1), S(O)₂R^(f1), or S(O)₂NR^(g1)R^(h1); or—(Y¹)_(q)—(R^(4a))_(r)—(Y²)_(s)—R^(4b) and—(X¹)_(m)—(R^(5a))_(n)—(X²)_(p)—R^(5b) together with the N atom to whichthey are attached form a 4- to 20-membered heterocycloalkyl groupoptionally substituted by 1, 2, 3, 4 or 5 substituents selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy⁴, CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(NR^(i))NR^(g1)R^(h1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); R⁶ is halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂, OR^(e2), SR^(e2),C(O)R^(f2), C(O)NR^(g2)R^(h2), C(O)OR^(e2), OC(O)R^(f2),OC(O)NR^(g2)R^(h2), NR^(g2)R^(h2), NR^(g2)C(O)R^(f2),NR^(g2)C(O)OR^(e2), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f2))₂, P(OR^(e2))₂,P(O)R^(e2)R^(f2), P(O)OR^(e2)OR^(f2), S(O)R^(f2), S(O)NR^(g2)R^(h2),S(O)₂R^(f2), or S(O)₂NR^(g2)R^(h2); R⁷ and R⁸ are independently selectedfrom H, C₁₋₈ alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,each optionally substituted by one or more substitutents independentlyselected from halo, CN, NO₂, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino,C₁₋₄ alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl; R^(8a) and R^(8b) are independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,arylalkyl, and cycloalkylalkyl; Cy¹, Cy², Cy³, and Cy⁴ are independentlyselected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, eachoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, CN, NO₂, OR^(e3), SR^(e3), C(O)R^(f3), C(O)NR^(g3)R^(h3),C(O)OR^(e3), OC(O)R^(f3), OC(O)NR^(g3)R^(h3), NR^(g3)R^(h3),NR^(g3)C(O)R^(h3), NR^(g3)C(O)OR^(e3), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f3))₂, P(OR^(e3))₂,P(O)R^(e3)R^(f3), P(O)OR^(e3)OR^(f3), S(O)R^(f3), S(O)NR^(g3)R^(h3),S(O)₂R^(f3), and S(O)₂NR^(g3)R^(h3); R^(a) and R^(b) are independentlyselected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂,OR^(e4), SR^(e4), C(O)R^(f4), C(O)NR^(g4)R^(h4), C(O)OR^(e4),OC(O)R^(f4), OC(O)NR^(g4)R^(h4), NR^(g4)R^(h4), NR^(g4)C(O)R^(h4),NR^(g4)C(O)OR^(e4), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f4))₂, P(OR^(e4))₂,P(O)R^(e4)R^(f4), P(O)OR^(e4)OR^(f4), S(O)R^(f4), S(O)NR^(g4)R^(h4),S(O)₂R^(f4), and S(O)₂NR^(g4)R^(h4); R^(c) is H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl; R^(d) is H, OR^(d1), CN or NO₂; R^(d1) is H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,arylalkyl, or cycloalkylalkyl; R^(e1), R^(e2), R^(e3), and R^(e4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,(C₁₋₆ alkoxy)-C₁₋₆ alkyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl andheterocycloalkylalkyl; R^(f1), R^(f2), R^(f3), and R^(f4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl; R^(g1),R^(g2), R^(g3), and R^(g4) are independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,arylalkyl, and cycloalkylalkyl; R^(h1), R^(h2), R^(h3), and R^(h4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, and cycloalkylalkyl; orR^(g1) and R^(h1) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group; or R^(g2) andR^(h3) together with the N atom to which they are attached form a 4-,5-, 6- or 7-membered heterocycloalkyl group; or R^(g3) and R^(h3)together with the N atom to which they are attached form a 4-, 5-, 6- or7-membered heterocycloalkyl group; or R^(g4) and R^(h4) together withthe N atom to which they are attached form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group; R^(i) is H, CN, or NO₂; a is 0 or 1; b is 0 or1; m is 0 or 1; n is 0 or 1; p is 0 or 1; q is 0 or 1; r is 0 or 1; s is0 or 1; t is 1, 2, 3, 4, 5 or 6; u is 0, 1, 2, 3, 4, 5 or 6; and v is 0,1, 2, 3, 4, 5 or
 6. 34. The method of claim 33 wherein said modulatingis inhibiting.
 35. A method of inhibiting immunosuppression in a patientcomprising administering to said patient an effective amount of acompound of Formula I:

or pharmaceutically acceptable salt form or prodrug thereof, wherein:Ring A is carbocyclyl or heterocyclyl optionally substituted by 1, 2, 3,4 or 5 R⁶; W, X¹, X², Y¹, and Y² are independently selected from(CR^(a)R^(b))_(t), (CR^(a)R^(b))_(u)O(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)O(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(S)(CR^(a)R^(b))_(u),(CR^(a)R^(b))_(u)C(S)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)₂(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)₂NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)NR^(c)(CR^(a)R^(b))_(v), and(CR^(a)R^(b))_(u)C(═NR^(d))NR^(c)(CR^(a)R^(b))_(v); R¹ is H, C(O)R⁷,C(O)NR^(8a)R^(8b), C(O)OR⁸, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, or heterocycloalkylalkyl; R² is H,C₁₋₆ alkyl, or C₃₋₇ cycloalkyl; R^(3a), R^(4a), and R^(5a) areindependently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy¹, CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); R^(3b), R^(4b),and R^(5b) are independently selected from H, C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, eachoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂, OR^(e1), SR^(e1),C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)R^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); or R² and—(R^(3a))_(a)—(W)_(b)—R^(3b) together with the N atom to which they areattached form a 4- to 20-membered heterocycloalkyl group optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy³, CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(O)NR^(g1)R^(h1), P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1),S(O)R^(f1), S(O)NR^(g1)R^(h1), S(O)₂R^(f1), or S(O)₂NR^(g1)R^(h1); or—(Y¹)_(q)—(R^(4a))_(r)—(Y²)_(s)—R^(4b) and—(X¹)_(m)—(R^(5a))_(n)—(X²)_(p)—R^(5b) together with the N atom to whichthey are attached form a 4- to 20-membered heterocycloalkyl groupoptionally substituted by 1, 2, 3, 4 or 5 substituents selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy⁴, CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(NR^(i))NR^(g1)R^(h1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); R⁶ is halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂, OR^(e2), SR^(e2),C(O)R^(f2), C(O)NR^(g2)R^(h2), C(O)OR^(e2), OC(O)R^(f2),OC(O)NR^(g2)R^(h2), NR^(g2)R^(h2), NR^(g2)C(O)R^(f2),NR^(g2)C(O)OR^(e2), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f2))₂, P(OR^(e2))₂,P(O)R^(e2)R^(f2), P(O)OR^(e2)OR^(f2), S(O)R^(f2), S(O)NR^(g2)R^(h2),S(O)₂R^(f2), or S(O)₂NR^(g2)R^(h2); R⁷ and R⁸ are independently selectedfrom H, C₁₋₈ alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,each optionally substituted by one or more substitutents independentlyselected from halo, CN, NO₂, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino,C₁₋₄ alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl; R^(8a) and R^(8b) are independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,arylalkyl, and cycloalkylalkyl; Cy¹, Cy², Cy³, and Cy⁴ are independentlyselected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, eachoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, CN, NO₂, OR^(e3), SR^(e3), C(O)R^(f3), C(O)NR^(g3)R^(h3),C(O)OR^(e3), OC(O)R^(f3), OC(O)NR^(g3)R^(h3), NR^(g3)R^(h3),NR^(g3)C(O)R^(h3), NR^(g3)C(O)OR^(e3), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f3))₂, P(OR^(e3))₂,P(O)R^(e3)R^(f3), P(O)OR^(e3)OR^(f3), S(O)R^(f3), S(O)NR^(g3)R^(h3),S(O)₂R^(f3), and S(O)₂NR^(g3)R^(h3); R^(a) and R^(b) are independentlyselected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂,OR^(e4), SR^(e4), C(O)R^(f4), C(O)NR^(g4)R^(h4), C(O)OR^(e4),OC(O)R^(f4), OC(O)NR^(g4)R^(h4), NR^(g4)R^(h4), NR^(g4)C(O)R^(h4),NR^(g4)C(O)OR^(e4), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f4))₂, P(OR^(e4))₂,P(O)R^(e4)R^(f4), P(O)OR^(e4)OR^(f4), S(O)R^(f4), S(O)NR^(g4)R^(h4),S(O)₂R^(f4), and S(O)₂NR^(g4)R^(h4); R^(c) is H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl; R^(d) is H, OR^(d1), CN or NO₂; R^(d1) is H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,arylalkyl, or cycloalkylalkyl; R^(e1), R^(e2), R^(e3), and R^(e4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,(C₁₋₆ alkoxy)-C₁₋₆ alkyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl andheterocycloalkylalkyl; R^(f1), R^(f2), R^(f3), and R^(f4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl; R^(g1),R^(g2), R^(g3), and R^(g4) are independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,arylalkyl, and cycloalkylalkyl; R^(h1), R^(h2), R^(h3), and R^(h4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, and cycloalkylalkyl; orR^(g1) and R^(h1) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group; or R^(g2) andR^(h3) together with the N atom to which they are attached form a 4-,5-, 6- or 7-membered heterocycloalkyl group; or R^(g3) and R^(h3)together with the N atom to which they are attached form a 4-, 5-, 6- or7-membered heterocycloalkyl group; or R^(g4) and R^(h4) together withthe N atom to which they are attached form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group; R^(i) is H, CN, or NO₂; a is 0 or 1; b is 0 or1; m is 0 or 1; n is 0 or 1; p is 0 or 1; q is 0 or 1; r is 0 or 1; s is0 or 1; t is 1, 2, 3, 4, 5 or 6; u is 0, 1, 2, 3, 4, 5 or 6; and v is 0,1, 2, 3, 4, 5 or
 6. 36. A method of treating cancer, viral infection,depression, a neurodegenerative disorder, trauma, age-related cataracts,organ transplant rejection, or an autoimmune disease in a patientcomprising administering to said patient a therapeutically effectiveamount of a compound of Formula I:

or pharmaceutically acceptable salt form or prodrug thereof, wherein:Ring A is carbocyclyl or heterocyclyl optionally substituted by 1, 2, 3,4 or 5 R⁶; W, X¹, X², Y¹, and Y² are independently selected from(CR^(a)R^(b))_(t), (CR^(a)R^(b))_(u)O(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(O)O(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)C(S)(CR^(a)R^(b))_(u),(CR^(a)R^(b))_(u)C(S)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)₂(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)S(O)₂NR^(c)(CR^(a)R^(b))_(v),(CR^(a)R^(b))_(u)NR^(c)(CR^(a)R^(b))_(v), and(CR^(a)R^(b))_(u)C(═NR^(d))NR^(c)(CR^(a)R^(b))_(v); R¹ is H, C(O)R⁷,C(O)NR^(8a)R^(8b), C(O)OR⁸, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, or heterocycloalkylalkyl; R² is H,C₁₋₆ alkyl, or C₃₋₇ cycloalkyl; R^(3a), R^(4a), and R^(5a) areindependently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy¹, CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); R^(3b), R^(4b),and R^(5b) are independently selected from H, C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, eachoptionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄haloalkyl, C₁₋₄ hydroxyalkyl, Cy², CN, NO₂, OR^(e1), SR^(e1),C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1), OC(O)R^(f1),OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1), NR^(g1)R^(h1),NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f1))₂, P(OR^(e1))₂,P(O)R^(e1)R^(f1), P(O)OR^(e1)R^(f1), S(O)R^(f1), S(O)NR^(g1)R^(h1),S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); or R² and—(R^(3a))_(a)—(W)_(b)—R^(3b) together with the N atom to which they areattached form a 4- to 20-membered heterocycloalkyl group optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy³, CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(O)NR^(g1)R^(h1), P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1),S(O)R^(f1), S(O)NR^(g1)R^(h1), S(O)₂R^(f1), or S(O)₂NR^(g1)R^(h1); or—(Y¹)_(q)—(R^(4a))_(r)—(Y²)_(s)—R^(4b) and—(X¹)_(m)—(R^(5a))_(n)—(X²)_(p)—R^(5b) together with the N atom to whichthey are attached form a 4- to 20-membered heterocycloalkyl groupoptionally substituted by 1, 2, 3, 4 or 5 substituents selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, Cy⁴, CN,NO₂, OR^(e1), SR^(e1), C(O)R^(f1), C(O)NR^(g1)R^(h1), C(O)OR^(e1),OC(O)R^(f1), OC(O)NR^(g1)R^(h1), NR^(g1)C(O)NR^(g1)R^(h1),NR^(g1)R^(h1), NR^(g1)C(O)R^(f1), NR^(g1)C(O)OR^(e1),C(═NR^(i))NR^(g1)R^(h1), NR^(g1)C(NR^(i))NR^(g1)R^(h1), P(R^(f1))₂,P(OR^(e1))₂, P(O)R^(e1)R^(f1), P(O)OR^(e1)OR^(f1), S(O)R^(f1),S(O)NR^(g1)R^(h1), S(O)₂R^(f1), and S(O)₂NR^(g1)R^(h1); R⁶ is halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂, OR^(e2), SR^(e2),C(O)R^(f2), C(O)NR^(g2)R^(h2), C(O)OR^(e2), OC(O)R^(f2),OC(O)NR^(g2)R^(h2), NR^(g2)R^(h2), NR^(g2)C(O)R^(f2),NR^(g2)C(O)OR^(e2), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f2))₂, P(OR^(e2))₂,P(O)R^(e2)R^(f2), P(O)OR^(e2)OR^(f2), S(O)R^(f2), S(O)NR^(g2)R^(h2),S(O)₂R^(f2), or S(O)₂NR^(g2)R^(h2); R⁷ and R⁸ are independently selectedfrom H, C₁₋₈ alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl,each optionally substituted by one or more halo, CN, NO₂, OH, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino, or C₂₋₈ dialkylamino,C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; R^(8a) and R^(8b) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, and cycloalkylalkyl; Cy¹,Cy², Cy³, and Cy⁴ are independently selected from aryl, heteroaryl,cycloalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3,4 or 5 substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, CN, NO₂, OR^(e3), SR^(e3),C(O)R^(f3), C(O)NR^(g3)R^(h3), C(O)OR^(e3), OC(O)R^(f3),OC(O)NR^(g3)R^(h3), NR^(g3)R^(h3), NR^(g3)C(O)R^(h3),NR^(g3)C(O)OR^(e3), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f3))₂, P(OR^(e3))₂,P(O)R^(e3)R^(f3), P(O)OR^(e3)OR^(f3), S(O)R^(f3), S(O)NR^(g3)R^(h3),S(O)₂R^(f3), and S(O)₂NR^(g3)R^(h3); R^(a) and R^(b) are independentlyselected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO₂,OR^(e4), SR^(e4), C(O)R^(f4), C(O)NR^(g4)R^(h4), C(O)OR^(e4),OC(O)R^(f4), OC(O)NR^(g4)R^(h4), NR^(g4)R^(h4), NR^(g4)C(O)R^(h4),NR^(g4)C(O)OR^(e4), C(═NR^(i))NR^(g1)R^(h1),NR^(g1)C(═NR^(i))NR^(g1)R^(h1), P(R^(f4))₂, P(OR^(e4))₂,P(O)R^(e4)R^(f4), P(O)OR^(e4)OR^(f4), S(O)R^(f4), S(O)NR^(g4)R^(h4),S(O)₂R^(f4), and S(O)₂NR^(g4)R^(h4); R^(c) is H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl; R^(d) is H, OR^(d1), CN or NO₂; R^(d1) is H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,arylalkyl, or cycloalkylalkyl; R^(e1), R^(e2), R^(e3), and R^(e4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,(C₁₋₆ alkoxy)-C₁₋₆ alkyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl andheterocycloalkylalkyl; R^(f1), R^(f2), R^(f3), and R^(f4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl; R^(g1),R^(g2), R^(g3), and R^(g4) are independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,arylalkyl, and cycloalkylalkyl; R^(h1), R^(h2), R^(h3), and R^(h4) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, and cycloalkylalkyl; orR^(g1) and R^(h1) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group; or R^(g2) andR^(h3) together with the N atom to which they are attached form a 4-,5-, 6- or 7-membered heterocycloalkyl group; or R^(g3) and R^(h3)together with the N atom to which they are attached form a 4-, 5-, 6- or7-membered heterocycloalkyl group; or R^(g4) and R^(h4) together withthe N atom to which they are attached form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group; a is 0 or 1; b is 0 or 1; m is 0 or 1; n is 0 or1; p is 0 or 1; q is 0 or 1; r is 0 or 1; s is 0 or 1; t is 1, 2, 3, 4,5 or 6; u is 0, 1, 2, 3, 4, 5 or 6; and v is 0, 1, 2, 3, 4, 5 or
 6. 37.The method of claim 36 further comprising administration of ananti-viral agent, a chemotherapeutic, an immunosuppressant, radiation,an anti-tumor vaccine, an anti-viral vaccine, cytokine therapy, or atyrosine kinase inhibitor.